BMC Structural Biology最新文献

{"title":"An analysis of oligomerization interfaces in transmembrane proteins","authors":"Jose M Duarte,&nbsp;Nikhil Biyani,&nbsp;Kumaran Baskaran,&nbsp;Guido Capitani","doi":"10.1186/1472-6807-13-21","DOIUrl":"https://doi.org/10.1186/1472-6807-13-21","url":null,"abstract":"<p>The amount of transmembrane protein (TM) structures solved to date is now large enough to attempt large scale analyses. In particular, extensive studies of oligomeric interfaces in the transmembrane region are now possible.</p><p>We have compiled the first fully comprehensive set of validated transmembrane protein interfaces in order to study their features and assess what differentiates them from their soluble counterparts.</p><p>The general features of TM interfaces do not differ much from those of soluble proteins: they are large, tightly packed and possess many interface core residues. In our set, membrane lipids were not found to significantly mediate protein-protein interfaces. Although no G protein-coupled receptor (GPCR) was included in the validated set, we analyzed the crystallographic dimerization interfaces proposed in the literature. We found that the putative dimer interfaces proposed for class A GPCRs do not show the usual patterns of stable biological interfaces, neither in terms of evolution nor of packing, thus they likely correspond to crystal interfaces. We cannot however rule out the possibility that they constitute transient or weak interfaces. In contrast we do observe a clear signature of biological interface for the proposed dimer of the class F human Smoothened receptor.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-21","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4698358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining structural and evolutionary modules in proteins: a community detection approach to explore sub-domain architecture","authors":"Jose Sergio Hleap,&nbsp;Edward Susko,&nbsp;Christian Blouin","doi":"10.1186/1472-6807-13-20","DOIUrl":"https://doi.org/10.1186/1472-6807-13-20","url":null,"abstract":"<p>Assessing protein modularity is important to understand protein evolution. Still the question of the existence of a sub-domain modular architecture remains. We propose a graph-theory approach with significance and power testing to identify modules in protein structures. In the first step, clusters are determined by optimizing the partition that maximizes the modularity score. Second, each cluster is tested for significance. Significant clusters are referred to as modules. Evolutionary modules are identified by analyzing homologous structures. Dynamic modules are inferred from sets of snapshots of molecular simulations. We present here a methodology to identify sub-domain architecture robustly, biologically meaningful, and statistically supported.</p><p>The robustness of this new method is tested using simulated data with known modularity. Modules are correctly identified even when there is a low correlation between landmarks within a module. We also analyzed the evolutionary modularity of a data set of <i>α</i>-amylase catalytic domain homologs, and the dynamic modularity of the Niemann-Pick C1 (NPC1) protein N-terminal domain.</p><p>The <i>α</i>-amylase contains an (<i>α</i>/<i>β</i>)₈ barrel (TIM barrel) with the polysaccharides cleavage site and a calcium-binding domain. In this data set we identified four robust evolutionary modules, one of which forms the minimal functional TIM barrel topology.</p><p>The NPC1 protein is involved in the intracellular lipid metabolism coordinating sterol trafficking. NPC1 N-terminus is the first luminal domain which binds to cholesterol and its oxygenated derivatives. Our inferred dynamic modules in the protein NPC1 are also shown to match functional components of the protein related to the NPC1 disease.</p><p>A domain compartmentalization can be found and described in correlation space. To our knowledge, there is no other method attempting to identify sub-domain architecture from the correlation among residues. Most attempts made focus on sequence motifs of protein-protein interactions, binding sites, or sequence conservancy. We were able to describe functional/structural sub-domain architecture related to key residues for starch cleavage, calcium, and chloride binding sites in the <i>α</i>-amylase, and sterol opening-defining modules and disease-related residues in the NPC1. We also described the evolutionary sub-domain architecture of the <i>α</i>-amylase catalytic domain, identifying the already reported minimum functional TIM barrel.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-20","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4661614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crystal structure of c5321: a protective antigen present in uropathogenic Escherichia coli strains displaying an SLR fold","authors":"Dunja Urosev,&nbsp;Mario Ferrer-Navarro,&nbsp;Ilaria Pastorello,&nbsp;Elena Cartocci,&nbsp;Lionel Costenaro,&nbsp;Dmitrijs Zhulenkovs,&nbsp;Jean-Didier Maréchal,&nbsp;Ainars Leonchiks,&nbsp;David Reverter,&nbsp;Laura Serino,&nbsp;Marco Soriani,&nbsp;Xavier Daura","doi":"10.1186/1472-6807-13-19","DOIUrl":"https://doi.org/10.1186/1472-6807-13-19","url":null,"abstract":"<p>Increasing rates of antimicrobial resistance among uropathogens led, among other efforts, to the application of subtractive reverse vaccinology for the identification of antigens present in extraintestinal pathogenic <i>E. coli</i> (ExPEC) strains but absent or variable in non-pathogenic strains, in a quest for a broadly protective <i>Escherichia coli</i> vaccine. The protein coded by locus <i>c5321</i> from CFT073 <i>E. coli</i> was identified as one of nine potential vaccine candidates against ExPEC and was able to confer protection with an efficacy of 33% in a mouse model of sepsis. c5321 (known also as EsiB) lacks functional annotation and structurally belongs to the Sel1-like repeat (SLR) family. Herein, as part of the general characterization of this potential antigen, we have focused on its structural properties.</p><p>We report the 1.74??-resolution crystal structure of c5321 from CFT073 <i>E. coli</i> determined by Se-Met SAD phasing. The structure is composed of 11 SLR units in a topological organisation that highly resembles that found in HcpC from <i>Helicobacter pylori,</i> with the main difference residing in how the super-helical fold is stabilised. The stabilising effect of disulfide bridges in HcpC is replaced in c5321 by a strengthening of the inter-repeat hydrophobic core. A metal-ion binding site, uncharacteristic of SLR proteins, is detected between SLR units 3 and 4 in the region of the inter-repeat hydrophobic core. Crystal contacts are observed between the C-terminal tail of one molecule and the C-terminal amphipathic groove of a neighbouring one, resembling interactions between ligand and proteins containing tetratricopeptide-like repeats.</p><p>The structure of antigen c5321 presents a mode of stabilization of the SLR fold different from that observed in close homologs of known structure. The location of the metal-ion binding site and the observed crystal contacts suggest a potential role in regulation of conformational flexibility and interaction with yet unidentified target proteins, respectively. These findings open new perspectives in both antigen design and for the identification of a functional role for this protective antigen.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4317710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular details of ligand selectivity determinants in a promiscuous β-glucan periplasmic binding protein","authors":"Parthapratim Munshi,&nbsp;Christopher B Stanley,&nbsp;Sudipa Ghimire-Rijal,&nbsp;Xun Lu,&nbsp;Dean A Myles,&nbsp;Matthew J Cuneo","doi":"10.1186/1472-6807-13-18","DOIUrl":"https://doi.org/10.1186/1472-6807-13-18","url":null,"abstract":"<p>Members of the periplasmic binding protein (PBP) superfamily utilize a highly conserved inter-domain ligand binding site that adapts to specifically bind a chemically diverse range of ligands. This paradigm of PBP ligand binding specificity was recently altered when the structure of the <i>Thermotoga maritima</i> cellobiose-binding protein (tmCBP) was solved. The tmCBP binding site is bipartite, comprising a canonical solvent-excluded region (subsite one), adjacent to a solvent-filled cavity (subsite two) where specific and semi-specific ligand recognition occur, respectively.</p><p>A molecular level understanding of binding pocket adaptation mechanisms that simultaneously allow both ligand specificity at subsite one and promiscuity at subsite two has potentially important implications in ligand binding and drug design studies. We sought to investigate the determinants of ligand binding selectivity in tmCBP through biophysical characterization of tmCBP in the presence of varying β-glucan oligosaccharides. Crystal structures show that whilst the amino acids that comprise both the tmCBP subsite one and subsite two binding sites remain fixed in conformation regardless of which ligands are present, the rich hydrogen bonding potential of water molecules may facilitate the ordering and the plasticity of this unique PBP binding site.</p><p>The identification of the roles these water molecules play in ligand recognition suggests potential mechanisms that can be utilized to adapt a single ligand binding site to recognize multiple distinct ligands.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-18","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4187759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosslinking and mass spectrometry suggest that the isolated NTD domain dimer of Moloney murine leukemia virus integrase adopts a parallel arrangement in solution","authors":"Daniel R Henriquez,&nbsp;Caifeng Zhao,&nbsp;Haiyan Zheng,&nbsp;José J Arbildua,&nbsp;Mónica L Acevedo,&nbsp;Monica J Roth,&nbsp;Oscar Leon","doi":"10.1186/1472-6807-13-14","DOIUrl":"https://doi.org/10.1186/1472-6807-13-14","url":null,"abstract":"<p>Retroviral integrases (INs) catalyze the integration of viral DNA in the chromosomal DNA of the infected cell. This reaction requires the multimerization of IN to coordinate a nucleophilic attack of the 3’ ends of viral DNA at two staggered phosphodiester bonds on the recipient DNA. Several models indicate that a tetramer of IN would be required for two-end concerted integration. Complementation assays have shown that the N-terminal domain (NTD) of integrase is essential for concerted integration, contributing to the formation of a multimer through protein-protein interaction. The isolated NTD of Mo-MLV integrase behave as a dimer in solution however the structure of the dimer in solution is not known.</p><p>In this work, crosslinking and mass spectrometry were used to identify regions involved in the dimerization of the isolated Mo-MLV NTD. The distances between the crosslinked lysines within the monomer are in agreement with the structure of the NTD monomer found in 3NNQ. The intermolecular crosslinked peptides corresponding to Lys 20-Lys 31, Lys 24-Lys 24 and Lys 68-Lys 88 were identified. The 3D coordinates of 3NNQ were used to derive a theoretical structure of the NTD dimer with the suite 3D-Dock, based on shape and electrostatics complementarity, and filtered with the distance restraints determined in the crosslinking experiments.</p><p>The crosslinking results are consistent with the monomeric structure of NTD in 3NNQ, but for the dimer, in our model both polypeptides are oriented in parallel with each other and the contacting areas between the monomers would involve the interactions between helices 1 and helices 3 and 4.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4758405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crystal structure of the C-terminal globular domain of the third paralog of the Archaeoglobus fulgidus oligosaccharyltransferases","authors":"Shunsuke Matsumoto,&nbsp;Atsushi Shimada,&nbsp;Daisuke Kohda","doi":"10.1186/1472-6807-13-11","DOIUrl":"https://doi.org/10.1186/1472-6807-13-11","url":null,"abstract":"<p>Protein N-glycosylation occurs in the three domains of life. Oligosaccharyltransferase (OST) transfers an oligosaccharide chain to the asparagine residue in the N-glycosylation sequons. The catalytic subunits of the OST enzyme are STT3 in eukaryotes, AglB in archaea and PglB in eubacteria. The genome of a hyperthermophilic archaeon, <i>Archaeoglobus fulgidus</i>, encodes three paralogous AglB proteins. We previously solved the crystal structures of the C-terminal globular domains of two paralogs, AglB-S<i>hort</i> 1 and AglB-S<i>hort</i> 2.</p><p>We determined the crystal structure of the C-terminal globular domain of the third AglB paralog, AglB-L<i>ong</i>, at 1.9?? resolutions. The crystallization of the fusion protein with maltose binding protein (MBP) afforded high quality protein crystals. Two MBP-AglB-L molecules formed a swapped dimer in the crystal. Since the fusion protein behaved as a monomer upon gel filtration, we reconstituted the monomer structure from the swapped dimer by exchanging the swapped segments. The C-terminal domain of <i>A. fulgidus</i> AglB-L includes a structural unit common to AglB-S1 and AglB-S2. This structural unit contains the evolutionally conserved WWDYG and DK motifs. The present structure revealed that <i>A. fulgidus</i> AglB-L contained a variant type of the DK motif with a short insertion, and confirmed that the second signature residue, Lys, of the DK motif participates in the formation of a pocket that binds to the serine and threonine residues at the +2 position of the N-glycosylation sequon.</p><p>The structure of <i>A. fulgidus</i> AglB-L, together with the two previously solved structures of AglB-S1 and AglB-S2, provides a complete overview of the three AglB paralogs encoded in the <i>A. fulgidus</i> genome. All three AglBs contain a variant type of the DK motif. This finding supports a previously proposed rule: The STT3/AglB/PglB paralogs in one organism always contain the same type of Ser/Thr-binding pocket. The present structure will be useful as a search model for molecular replacement in the structural determination of the full-length <i>A. fulgidus</i> AglB-L.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4028748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A structural role for the PHP domain in E. coli DNA polymerase III","authors":"Tiago Barros,&nbsp;Joel Guenther,&nbsp;Brian Kelch,&nbsp;Jordan Anaya,&nbsp;Arjun Prabhakar,&nbsp;Mike O’Donnell,&nbsp;John Kuriyan,&nbsp;Meindert H Lamers","doi":"10.1186/1472-6807-13-8","DOIUrl":"https://doi.org/10.1186/1472-6807-13-8","url":null,"abstract":"<p>In addition to the core catalytic machinery, bacterial replicative DNA polymerases contain a Polymerase and Histidinol Phosphatase (PHP) domain whose function is not entirely understood. The PHP domains of some bacterial replicases are active metal-dependent nucleases that may play a role in proofreading. In <i>E. coli</i> DNA polymerase III, however, the PHP domain has lost several metal-coordinating residues and is likely to be catalytically inactive.</p><p>Genomic searches show that the loss of metal-coordinating residues in polymerase PHP domains is likely to have coevolved with the presence of a separate proofreading exonuclease that works with the polymerase. Although the <i>E. coli</i> Pol III PHP domain has lost metal-coordinating residues, the structure of the domain has been conserved to a remarkable degree when compared to that of metal-binding PHP domains. This is demonstrated by our ability to restore metal binding with only three point mutations, as confirmed by the metal-bound crystal structure of this mutant determined at 2.9 ? resolution. We also show that Pol III, a large multi-domain protein, unfolds cooperatively and that mutations in the degenerate metal-binding site of the PHP domain decrease the overall stability of Pol III and reduce its activity.</p><p>While the presence of a PHP domain in replicative bacterial polymerases is strictly conserved, its ability to coordinate metals and to perform proofreading exonuclease activity is not, suggesting additional non-enzymatic roles for the domain. Our results show that the PHP domain is a major structural element in Pol III and its integrity modulates both the stability and activity of the polymerase.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4585396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and functional studies of S-adenosyl-L-methionine binding proteins: a ligand-centric approach","authors":"Rajaram Gana,&nbsp;Shruti Rao,&nbsp;Hongzhan Huang,&nbsp;Cathy Wu,&nbsp;Sona Vasudevan","doi":"10.1186/1472-6807-13-6","DOIUrl":"https://doi.org/10.1186/1472-6807-13-6","url":null,"abstract":"<p>The post-genomic era poses several challenges. The biggest is the identification of biochemical function for protein sequences and structures resulting from genomic initiatives. Most sequences lack a characterized function and are annotated as hypothetical or uncharacterized. While homology-based methods are useful, and work well for sequences with sequence identities above 50%, they fail for sequences in the twilight zone (&lt;30%) of sequence identity. For cases where sequence methods fail, structural approaches are often used, based on the premise that structure preserves function for longer evolutionary time-frames than sequence alone. It is now clear that no single method can be used successfully for functional inference. Given the growing need for functional assignments, we describe here a systematic new approach, designated ligand-centric, which is primarily based on analysis of ligand-bound/unbound structures in the PDB. Results of applying our approach to S-adenosyl-L-methionine (SAM) binding proteins are presented.</p><p>Our analysis included 1,224 structures that belong to 172 unique families of the Protein Information Resource Superfamily system. Our ligand-centric approach was divided into four levels: residue, protein/domain, ligand, and family levels. The residue level included the identification of conserved binding site residues based on structure-guided sequence alignments of representative members of a family, and the identification of conserved structural motifs. The protein/domain level included structural classification of proteins, Pfam domains, domain architectures, and protein topologies. The ligand level included ligand conformations, ribose sugar puckering, and the identification of conserved ligand-atom interactions. The family level included phylogenetic analysis.</p><p>We found that SAM bound to a total of 18 different fold types (I-XVIII). We identified 4 new fold types and 11 additional topological arrangements of strands within the well-studied Rossmann fold Methyltransferases (MTases). This extends the existing structural classification of SAM binding proteins. A striking correlation between fold type and the conformation of the bound SAM (classified as types) was found across the 18 fold types. Several site-specific rules were created for the assignment of functional residues to families and proteins that do not have a bound SAM or a solved structure.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5312835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis for hypermodification of the wobble uridine in tRNA by bifunctional enzyme MnmC","authors":"Jungwook Kim,&nbsp;Steven C Almo","doi":"10.1186/1472-6807-13-5","DOIUrl":"https://doi.org/10.1186/1472-6807-13-5","url":null,"abstract":"<p>Methylaminomethyl modification of uridine or 2-thiouridine (mnm5U34 or mnm5s2U34) at the wobble position of tRNAs specific for glutamate, lysine and arginine are observed in <i>Escherichia coli</i> and allow for specific recognition of codons ending in A or G. In the biosynthetic pathway responsible for this post-transcriptional modification, the bifunctional enzyme MnmC catalyzes the conversion of its hypermodified substrate carboxymethylaminomethyl uridine (cmnm5U34) to mnm5U34. MnmC catalyzes the flavin adenine dinucleotide (FAD)-dependent oxidative cleavage of carboxymethyl group from cmnm5U34 via an imine intermediate to generate aminomethyl uridine (nm5U34), which is subsequently methylated by S-adenosyl-L-methionine (SAM) to yield methylaminomethyl uridine (mnm5U34).</p><p>The X-ray crystal structures of SAM/FAD-bound bifunctional MnmC from <i>Escherichia coli</i> and <i>Yersinia pestis</i>, and FAD-bound bifunctional MnmC from <i>Yersinia pestis</i> were determined and the catalytic functions verified in an <i>in vitro</i> assay.</p><p>The crystal structures of MnmC from two Gram negative bacteria reveal the overall architecture of the enzyme and the relative disposition of the two independent catalytic domains: a Rossmann-fold domain containing the SAM binding site and an FAD containing domain structurally homologous to glycine oxidase from <i>Bacillus subtilis</i>. The structures of MnmC also reveal the detailed atomic interactions at the interdomain interface and provide spatial restraints relevant to the overall catalytic mechanism.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4916457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disturbance of DNA conformation by the binding of testosterone-based platinum drugs via groove-face and intercalative interactions: a molecular dynamics simulation study","authors":"Shanshan Cui,&nbsp;Yan Wang,&nbsp;Guangju Chen","doi":"10.1186/1472-6807-13-4","DOIUrl":"https://doi.org/10.1186/1472-6807-13-4","url":null,"abstract":"<p>To explore novel platinum-based anticancer agents that are distinct from the structure and interaction mode of the traditional cisplatin by forming the bifunctional intrastrand 1,2 GpG adduct, the monofunctional platinum?+?DNA adducts with extensive non-covalent interactions had been studied. It was reported that the monofunctional testosterone-based platinum(II) agents present the high anticancer activity. Moreover, it was also found that the testosterone-based platinum agents could cause the DNA helix to undergo significant unwinding and bending over the non-testosterone-based platinum agents. However, the interaction mechanisms of these platinum agents with DNA at the atomic level are not yet clear so far.</p><p>In the present work, we used molecular dynamics (MD) simulations and DNA conformational dynamics calculations to study the DNA distortion properties of the testosterone-based platinum?+?DNA, the improved testosterone-based platinum?+?DNA and the non-testosterone-based platinum?+?DNA adducts. The results show that the intercalative interaction of the improved flexible testosterone-based platinum agent with DNA molecule could cause larger DNA conformational distortion than the groove-face interaction of the rigid testosterone-based platinum agent with DNA molecule. Further investigations for the non-testosterone-based platinum agent reveal the occurrence of insignificant change of DNA conformation due to the absence of testosterone ligand in such agent. Based on the DNA dynamics analysis, the DNA base motions relating to DNA groove parameter changes and hydrogen bond destruction of DNA base pairs were also discussed in this work.</p><p>The flexible linker in the improved testosterone-based platinum agent causes an intercalative interaction with DNA in the improved testosterone-based platinum?+?DNA adduct, which is different from the groove-face interaction caused by a rigid linker in the testosterone-based platinum agent. The present investigations provide useful information of DNA conformation affected by a testosterone-based platinum complex at the atomic level.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"13 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2013-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6807-13-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4866703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}