BMC Structural Biology最新文献

{"title":"REFOLDdb: a new and sustainable gateway to experimental protocols for protein refolding","authors":"Hisashi Mizutani,&nbsp;Hideaki Sugawara,&nbsp;Ashley M. Buckle,&nbsp;Takeshi Sangawa,&nbsp;Ken-ichi Miyazono,&nbsp;Jun Ohtsuka,&nbsp;Koji Nagata,&nbsp;Tomoki Shojima,&nbsp;Shohei Nosaki,&nbsp;Yuqun Xu,&nbsp;Delong Wang,&nbsp;Xiao Hu,&nbsp;Masaru Tanokura,&nbsp;Kei Yura","doi":"10.1186/s12900-017-0074-z","DOIUrl":"https://doi.org/10.1186/s12900-017-0074-z","url":null,"abstract":"<p>More than 7000 papers related to “protein refolding” have been published to date, with approximately 300 reports each year during the last decade. Whilst some of these papers provide experimental protocols for protein refolding, a survey in the structural life science communities showed a necessity for a comprehensive database for refolding techniques. We therefore have developed a new resource – “REFOLDdb” that collects refolding techniques into a single, searchable repository to help researchers develop refolding protocols for proteins of interest.</p><p>We based our resource on the existing REFOLD database, which has not been updated since 2009. We redesigned the data format to be more concise, allowing consistent representations among data entries compared with the original REFOLD database. The remodeled data architecture enhances the search efficiency and improves the sustainability of the database. After an exhaustive literature search we added experimental refolding protocols from reports published 2009 to early 2017. In addition to this new data, we fully converted and integrated existing REFOLD data into our new resource. REFOLDdb contains 1877 entries as of March 17^th, 2017, and is freely available at http://p4d-info.nig.ac.jp/refolddb/.</p><p>REFOLDdb is a unique database for the life sciences research community, providing annotated information for designing new refolding protocols and customizing existing methodologies. We envisage that this resource will find wide utility across broad disciplines that rely on the production of pure, active, recombinant proteins. Furthermore, the database also provides a useful overview of the recent trends and statistics in refolding technology development.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"17 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2017-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-017-0074-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4922112","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 comparative analysis of the foamy and ortho virus capsid structures reveals an ancient domain duplication","authors":"William R. Taylor,&nbsp;Jonathan P. Stoye,&nbsp;Ian A. Taylor","doi":"10.1186/s12900-017-0073-0","DOIUrl":"https://doi.org/10.1186/s12900-017-0073-0","url":null,"abstract":"<p>The <i>Spumaretrovirinae</i> (foamy viruses) and the <i>Orthoretrovirinae</i> (e.g. HIV) share many similarities both in genome structure and the sequences of the core viral encoded proteins, such as the aspartyl protease and reverse transcriptase. Similarity in the <i>gag</i> region of the genome is less obvious at the sequence level but has been illuminated by the recent solution of the foamy virus capsid (CA) structure. This revealed a clear structural similarity to the orthoretrovirus capsids but with marked differences that left uncertainty in the relationship between the two domains that comprise the structure.</p><p>We have applied protein structure comparison methods in order to try and resolve this ambiguous relationship. These included both the <span>DALI</span> method and the <span>SAP</span> method, with rigorous statistical tests applied to the results of both methods. For this, we employed collections of artificial fold ’decoys’ (generated from the pair of native structures being compared) to provide a customised background distribution for each comparison, thus allowing significance levels to be estimated.</p><p>We have shown that the relationship of the two domains conforms to a simple linear correspondence rather than a domain transposition. These similarities suggest that the origin of both viral capsids was a common ancestor with a double domain structure. In addition, we show that there is also a significant structural similarity between the amino and carboxy domains in both the foamy and ortho viruses.</p><p>These results indicate that, as well as the duplication of the double domain capsid, there may have been an even more ancient gene-duplication that preceded the double domain structure. In addition, our structure comparison methodology demonstrates a general approach to problems where the components have a high intrinsic level of similarity.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"17 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2017-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-017-0073-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4146596","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":"DynaDom: structure-based prediction of T cell receptor inter-domain and T cell receptor-peptide-MHC (class I) association angles","authors":"Thomas Hoffmann,&nbsp;Antoine Marion,&nbsp;Iris Antes","doi":"10.1186/s12900-016-0071-7","DOIUrl":"https://doi.org/10.1186/s12900-016-0071-7","url":null,"abstract":"<p>T cell receptor (TCR) molecules are involved in the adaptive immune response as they distinguish between self- and foreign-peptides, presented in major histocompatibility complex molecules (pMHC). Former studies showed that the association angles of the TCR variable domains (Vα/Vβ) can differ significantly and change upon binding to the pMHC complex. These changes can be described as a rotation of the domains around a general Center of Rotation, characterized by the interaction of two highly conserved glutamine residues.</p><p>We developed a computational method, DynaDom, for the prediction of TCR Vα/Vβ inter-domain and TCR/pMHC orientations in TCRpMHC complexes, which allows predicting the orientation of multiple protein-domains. In addition, we implemented a new approach to predict the correct orientation of the carboxamide endgroups in glutamine and asparagine residues, which can also be used as an external, independent tool.</p><p>The approach was evaluated for the remodeling of 75 and 53 experimental structures of TCR and TCRpMHC (class I) complexes, respectively. We show that the DynaDom method predicts the correct orientation of the TCR Vα/Vβ angles in 96 and 89% of the cases, for the poses with the best RMSD and best interaction energy, respectively. For the concurrent prediction of the TCR Vα/Vβ and pMHC orientations, the respective rates reached 74 and 72%. Through an exhaustive analysis, we could show that the pMHC placement can be further improved by a straightforward, yet very time intensive extension of the current approach.</p><p>The results obtained in the present remodeling study prove the suitability of our approach for interdomain-angle optimization. In addition, the high prediction rate obtained specifically for the energetically highest ranked poses further demonstrates that our method is a powerful candidate for blind prediction. Therefore it should be well suited as part of any accurate atomistic modeling pipeline for TCRpMHC complexes and potentially other large molecular assemblies.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"17 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2017-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-016-0071-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4076237","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":"Prokaryotic ubiquitin-like protein remains intrinsically disordered when covalently attached to proteasomal target proteins","authors":"Jonas Barandun,&nbsp;Fred F. Damberger,&nbsp;Cyrille L. Delley,&nbsp;Juerg Laederach,&nbsp;Frédéric H. T. Allain,&nbsp;Eilika Weber-Ban","doi":"10.1186/s12900-017-0072-1","DOIUrl":"https://doi.org/10.1186/s12900-017-0072-1","url":null,"abstract":"<p>The post-translational modification pathway referred to as pupylation marks proteins for proteasomal degradation in <i>Mycobacterium tuberculosis</i> and other actinobacteria by covalently attaching the small protein Pup (prokaryotic ubiquitin-like protein) to target lysine residues. In contrast to the functionally analogous eukaryotic ubiquitin, Pup is intrinsically disordered in its free form. Its unfolded state allows Pup to adopt different structures upon interaction with different binding partners like the Pup ligase PafA and the proteasomal ATPase Mpa. While the disordered behavior of free Pup has been well characterized, it remained unknown whether Pup adopts a distinct structure when attached to a substrate.</p><p>Using a combination of NMR experiments and biochemical analysis we demonstrate that Pup remains unstructured when ligated to two well-established pupylation substrates targeted for proteasomal degradation in <i>Mycobacterium tuberculosis</i>, malonyl transacylase (FabD) and ketopantoyl hydroxylmethyltransferase (PanB). Isotopically labeled Pup was linked to FabD and PanB by in vitro pupylation to generate homogeneously pupylated substrates suitable for NMR analysis. The single target lysine of PanB was identified by a combination of mass spectroscopy and mutational analysis. Chemical shift comparison between Pup?in its free form and ligated to substrate reveals intrinsic disorder of Pup in the conjugate.</p><p>When linked to the proteasomal substrates FabD and PanB, Pup is unstructured and retains the ability to interact with its different binding partners. This suggests that it is?not the conformation of Pup attached to these two substrates which determines their delivery to the proteasome,?but the availability of the degradation complex and the depupylase.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"17 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-017-0072-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4020506","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":"Endocrine disruption: In silico perspectives of interactions of di-(2-ethylhexyl)phthalate and its five major metabolites with progesterone receptor","authors":"Ishfaq A. Sheikh,&nbsp;Muhammad Abu-Elmagd,&nbsp;Rola F. Turki,&nbsp;Ghazi A. Damanhouri,&nbsp;Mohd A. Beg,&nbsp;Mohammed Al-Qahtani","doi":"10.1186/s12900-016-0066-4","DOIUrl":"https://doi.org/10.1186/s12900-016-0066-4","url":null,"abstract":"<p>Di-(2-ethylhexyl)phthalate (DEHP) is a common endocrine disrupting compound (EDC) present in the environment as a result of industrial activity and leaching from polyvinyl products. DEHP is used as a plasticizer in medical devices and many commercial and household items. Exposure occurs through inhalation, ingestion, and skin contact. DEHP is metabolized to a primary metabolite mono-(2-ethylhexyl)phthalate (MEHP) in the body, which is further metabolized to four major secondary metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5-OH-MEHP), mono(2-ethyl-5-oxyhexyl)phthalate (5-oxo-MEHP), mono(2-ethyl-5-carboxypentyl)phthalate (5-cx-MEPP) and mono[2-(carboxymethyl)hexyl]phthalate (2-cx-MMHP). DEHP and its metabolites are associated with developmental abnormalities and reproductive dysfunction within the human population. Progesterone receptor (PR) signaling is involved in important reproductive functions and is a potential target for endocrine disrupting activities of DEHP and its metabolites. This study used <i>in silico</i> approaches for structural binding analyses of DEHP and its five indicated major metabolites with PR.</p><p>Protein Data bank was searched to retrieve the crystal structure of human PR (Id: 1SQN). PubChem database was used to obtain the structures of DEHP and its five metabolites. Docking was performed using Glide (Schrodinger) Induced Fit Docking module.</p><p>DEHP and its metabolites interacted with 19-25 residues of PR with the majority of the interacting residues overlapping (82-95?% commonality) with the native bound ligand norethindrone (NET). DEHP and each of its five metabolites formed a hydrogen bonding interaction with residue Gln-725 of PR. The binding affinity was highest for NET followed by DEHP, 5-OH-MEHP, 5-oxo-MEHP, MEHP, 5-cx-MEPP, and 2-cx-MMHP.</p><p>The high binding affinity of DEHP and its five major metabolites with PR as well as a high rate of overlap between PR interacting residues among DEHP and its metabolites and the native ligand, NET, suggested their disrupting potential in normal PR signaling, resulting in adverse reproductive effects.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"16 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2016-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-016-0066-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5168927","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 lack of peptide binding and decreased thermostability suggests that the CASKIN2 scaffolding protein SH3 domain may be vestigial","authors":"Jamie J. Kwan,&nbsp;Logan W. Donaldson","doi":"10.1186/s12900-016-0065-5","DOIUrl":"https://doi.org/10.1186/s12900-016-0065-5","url":null,"abstract":"<p>CASKIN2 is a neuronal signaling scaffolding protein comprised of multiple ankyrin repeats, two SAM domains, and one SH3 domain. The CASKIN2 SH3 domain for an NMR structural determination because its peptide-binding cleft appeared to deviate from the repertoire of aromatic enriched amino acids that typically bind polyproline-rich sequences.</p><p>The structure demonstrated that two non-canonical basic amino acids (K290/R319) in the binding cleft were accommodated well in the SH3 fold. An K290Y/R319W double mutant restoring the typical aromatic amino acids found in the binding cleft resulted in a 20?°C relative increase in the thermal stability. Considering the reduced stability, we speculated that the CASKIN2 SH3 could be a nonfunctional remnant in this scaffolding protein.</p><p>While the NMR structure demonstrates that the CASKIN2 SH3 domain is folded, its cleft has suffered two substitutions that prevent it from binding typical polyproline ligands. This observation led us to additionally survey and describe other SH3 domains in the Protein Data Bank that may have similarly lost their ability to promote protein-protein interactions.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"16 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2016-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-016-0065-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4558840","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":"3D QSAR, pharmacophore and molecular docking studies of known inhibitors and designing of novel inhibitors for M18 aspartyl aminopeptidase of Plasmodium falciparum","authors":"Madhulata Kumari,&nbsp;Subhash Chandra,&nbsp;Neeraj Tiwari,&nbsp;Naidu Subbarao","doi":"10.1186/s12900-016-0063-7","DOIUrl":"https://doi.org/10.1186/s12900-016-0063-7","url":null,"abstract":"<p>The <i>Plasmodium falciparum</i> M18 Aspartyl Aminopeptidase (<i>Pf</i>M18AAP) is only aspartyl aminopeptidase which is found in the genome of <i>P. falciparum</i> and is essential for its survival. The <i>Pf</i>M18AAP enzyme performs various functions in the parasite and the erythrocytic host such as hemoglobin digestion, erythrocyte invasion, parasite growth and parasite escape from the host cell. It is a valid target to develop antimalarial drugs. In the present work, we employed 3D QSAR modeling, pharmacophore modeling, and molecular docking to identify novel potent inhibitors that bind with M18AAP of <i>P. falciparum</i>.</p><p>The PLSR QSAR model showed highest value for correlation coefficient r² (88?%) and predictive correlation coefficient (pred_r2) =0.6101 for external test set among all QSAR models. The pharmacophore modeling identified DHRR (one hydrogen donor, one hydrophobic group, and two aromatic rings) as an essential feature of <i>Pf</i>M18AAP inhibitors. The combined approach of 3D QSAR, pharmacophore, and structure-based molecular docking yielded 10 novel <i>Pf</i>M18AAP inhibitors from ChEMBL antimalarial library, 2 novel inhibitors from each derivative of quinine, chloroquine, 8-aminoquinoline and 10 novel inhibitors from WHO antimalarial drugs. Additionally, high throughput virtual screening identified top 10 compounds as antimalarial leads showing G-scores -12.50 to -10.45 (in kcal/mol), compared with control compounds(G-scores -7.80 to -4.70) which are known antimalarial M18AAP inhibitors (AID743024). This result indicates these novel compounds have the best binding affinity for <i>Pf</i>M18AAP.</p><p>The 3D QSAR models of <i>Pf</i>M18AAP inhibitors provided useful information about the structural characteristics of inhibitors which are contributors of the inhibitory potency. Interestingly, In this studies, we extrapolate that the derivatives of quinine, chloroquine, and 8-aminoquinoline, for which there is no specific target has been identified till date, might show the antimalarial effect by interacting with <i>Pf</i>M18AAP.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"16 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2016-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-016-0063-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4670169","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":"Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor","authors":"Hiroyuki Nojima,&nbsp;Kazuhiko Kanou,&nbsp;Genki Terashi,&nbsp;Mayuko Takeda-Shitaka,&nbsp;Gaku Inoue,&nbsp;Koichiro Atsuda,&nbsp;Chihiro Itoh,&nbsp;Chie Iguchi,&nbsp;Hajime Matsubara","doi":"10.1186/s12900-016-0062-8","DOIUrl":"https://doi.org/10.1186/s12900-016-0062-8","url":null,"abstract":"<p>We comprehensively analyzed X-ray cocrystal structures of dipeptidyl peptidase IV (DPP-4) and its inhibitor to clarify whether DPP-4 alters its general or partial structure according to the inhibitor used and whether DPP-4 has a common rule for inhibitor binding.</p><p>All the main and side chains in the inhibitor binding area were minimally altered, except for a few side chains, despite binding to inhibitors of various shapes. Some residues (Arg125, Glu205, Glu206, Tyr662 and Asn710) in the area had binding modes to fix a specific atom of inhibitor to a particular spatial position in DPP-4. We found two specific water molecules that were common to 92 DPP-4 structures. The two water molecules were close to many inhibitors, and seemed to play two roles: maintaining the orientation of the Glu205 and Glu206 side chains through a network via the water molecules, and arranging the inhibitor appropriately at the S2 subsite.</p><p>Our study based on high-quality resources may provide a necessary minimum consensus to help in the discovery of a novel DPP-4 inhibitor that is commercially useful.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"16 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2016-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-016-0062-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4197177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of human and mouse E-selectin binding to Sialyl-Lewisx","authors":"Anne D. Rocheleau,&nbsp;Thong M. Cao,&nbsp;Tait Takitani,&nbsp;Michael R. King","doi":"10.1186/s12900-016-0060-x","DOIUrl":"https://doi.org/10.1186/s12900-016-0060-x","url":null,"abstract":"<p>During inflammation, leukocytes are captured by the selectin family of adhesion receptors lining blood vessels to facilitate exit from the bloodstream. E-selectin is upregulated on stimulated endothelial cells and binds to several ligands on the surface of leukocytes. Selectin:ligand interactions are mediated in part by the interaction between the lectin domain and Sialyl-Lewis x (sLe^x), a tetrasaccharide common to selectin ligands. There is a high degree of homology between selectins of various species: about 72 and 60?% in the lectin and EGF domains, respectively. In this study, molecular dynamics, docking, and steered molecular dynamics simulations were used to compare the binding and dissociation mechanisms of sLe^x with mouse and human E-selectin. First, a mouse E-selectin homology model was generated using the human E-selectin crystal structure as a template.</p><p>Mouse E-selectin was found to have a greater interdomain angle, which has been previously shown to correlate with stronger binding among selectins. sLe^x was docked onto human and mouse E-selectin, and the mouse complex was found to have a higher free energy of binding and a lower dissociation constant, suggesting stronger binding. The mouse complex had higher flexibility in a few key residues. Finally, steered molecular dynamics was used to dissociate the complexes at force loading rates of 2000–5000?pm/ps². The mouse complex took longer to dissociate at every force loading rate and the difference was statistically significant at 3000?pm/ps². When sLe^x-coated microspheres were perfused through microtubes coated with human or mouse E-selectin, the particles rolled more slowly on mouse E-selectin.</p><p>Both molecular dynamics simulations and microsphere adhesion experiments show that mouse E-selectin protein binds more strongly to sialyl Lewis x ligand than human E-selectin. This difference was explained by a greater interdomain angle for mouse E-selectin, and greater flexibility in key residues. Future work could introduce similar amino acid substitutions into the human E-selectin sequence to further modulate adhesion behavior.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"16 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2016-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-016-0060-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4083439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crystal structure of human S100A8 in complex with zinc and calcium","authors":"Haili Lin,&nbsp;Gregers Rom Andersen,&nbsp;Laure Yatime","doi":"10.1186/s12900-016-0058-4","DOIUrl":"https://doi.org/10.1186/s12900-016-0058-4","url":null,"abstract":"<p>S100 proteins are a large family of calcium binding proteins present only in vertebrates. They function intra- and extracellularly both as regulators of homeostatic processes and as potent effectors during inflammation. Among these, S100A8 and S100A9 are two major constituents of neutrophils that can assemble into homodimers, heterodimers and higher oligomeric species, including fibrillary structures found in the ageing prostate. Each of these forms assumes specific functions and their formation is dependent on divalent cations, notably calcium and zinc. In particular, zinc appears as a major regulator of S100 protein function in a disease context. Despite this central role, no structural information on how zinc bind to S100A8/S100A9 and regulates their quaternary structure is yet available.</p><p>Here we report two crystallographic structures of calcium and zinc-loaded human S100A8. S100A8 binds two zinc ions per homodimer, through two symmetrical, all-His tetracoordination sites, revealing a classical His-Zn binding mode for the protein. Furthermore, the presence of a (Zn)₂-cacodylate complex in our second crystal form induces ligand swapping within the canonical His₄ zinc binding motif, thereby creating two new Zn-sites, one of which involves residues from symmetry-related molecules. Finally, we describe the calcium-induced S100A8 tetramer and reveal how zinc stabilizes this tetramer by tightening the dimer-dimer interface.</p><p>Our structures of Zn²⁺/Ca²⁺-bound hS100A8 demonstrate that S100A8 is a genuine His-Zn S100 protein. Furthermore, they show how zinc stabilizes S100A8 tetramerization and potentially mediates the formation of novel interdimer interactions. We propose that these zinc-mediated interactions may serve as a basis for the generation of larger oligomers in vivo.</p>","PeriodicalId":498,"journal":{"name":"BMC Structural Biology","volume":"16 1","pages":""},"PeriodicalIF":2.222,"publicationDate":"2016-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12900-016-0058-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4035145","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}