Current Research in Structural Biology最新文献

{"title":"Doxorubicin catalyses self-assembly of p53 by phase separation","authors":"Ankush Garg ,&nbsp;Gaurav Kumar ,&nbsp;Varinder Singh ,&nbsp;Sharmistha Sinha","doi":"10.1016/j.crstbi.2024.100133","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100133","url":null,"abstract":"<div><p>Liquid-liquid phase separation plays a crucial role in cellular physiology, as it leads to the formation of membrane-less organelles in response to various internal stimuli, contributing to various cellular functions. However, the influence of exogenous stimuli on this process in the context of disease intervention remains unexplored. In this current investigation, we explore the impact of doxorubicin on the abnormal self-assembly of p53 using a combination of biophysical and imaging techniques. Additionally, we shed light on the potential mechanisms behind chemoresistance in cancer cells carrying mutant p53.</p><p>Our findings reveal that doxorubicin co-localizes with both wild-type p53 (WTp53) and its mutant variants. Our <em>in vitro</em> experiments indicate that doxorubicin interacts with the N-terminal-deleted form of WTp53 (WTp53ΔNterm), inducing liquid-liquid phase separation, ultimately leading to protein aggregation. Notably, the p53 variants at the R273 position exhibit a propensity for phase separation even in the absence of doxorubicin, highlighting the destabilizing effects of point mutations at this position.</p><p>The strong interaction between doxorubicin and p53 variants, along with its localization within the protein condensates, provides a potential explanation for the development of chemotherapy resistance. Collectively, our cellular and <em>in vitro</em> studies emphasize the role of exogenous agents in driving phase separation-mediated p53 aggregation.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100133"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000102/pdfft?md5=42fe7a839b8535990a75792d8a30bcc4&pid=1-s2.0-S2665928X24000102-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139936977","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 insights into the disulfide isomerase and chaperone activity of TrbB of the F plasmid type IV secretion system","authors":"Arnold J. Apostol ,&nbsp;Nicholas J. Bragagnolo ,&nbsp;Christina S. Rodriguez ,&nbsp;Gerald F. Audette","doi":"10.1016/j.crstbi.2024.100156","DOIUrl":"10.1016/j.crstbi.2024.100156","url":null,"abstract":"<div><p>Bacteria have evolved elaborate mechanisms to thrive in stressful environments. F-like plasmids in gram-negative bacteria encode for a multi-protein Type IV Secretion System (T4SS_F) that is functional for bacterial proliferation and adaptation through the process of conjugation. The periplasmic protein TrbB is believed to have a stabilizing chaperone role in the T4SS_F assembly, with TrbB exhibiting disulfide isomerase (DI) activity. In the current report, we demonstrate that the deletion of the disordered N-terminus of TrbB_WT, resulting in a truncation construct TrbB_37-161, does not affect its catalytic <em>in vitro</em> activity compared to the wild-type protein (p = 0.76). Residues W37–K161, which include the active thioredoxin motif, are sufficient for DI activity. The N-terminus of TrbB_WT is disordered as indicated by a structural model of GST-TrbB_WT based on ColabFold-AlphaFold2 and Small Angle X-Ray Scattering data and ¹H–¹⁵N Heteronuclear Single Quantum Correlation (HSQC) spectroscopy of the untagged protein. This disordered region likely contributes to the protein's dynamicity; removal of this region results in a more stable protein based on ¹H–¹⁵N HSQC and Circular Dichroism Spectroscopies. Lastly, size exclusion chromatography analysis of TrbB_WT in the presence of TraW, a T4SS_F assembly protein predicted to interact with TrbB_WT, does not support the inference of a stable complex forming <em>in vitro</em>. This work advances our understanding of TrbB's structure and function, explores the role of structural disorder in protein dynamics in the context of a T4SS_F accessory protein, and highlights the importance of redox-assisted protein folding in the T4SS_F.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"8 ","pages":"Article 100156"},"PeriodicalIF":2.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000333/pdfft?md5=dd89ce99d737f5e271b30cb1909da8ae&pid=1-s2.0-S2665928X24000333-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141637070","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":"Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery","authors":"Vandana Mishra ,&nbsp;Anuradha Deshmukh ,&nbsp;Ishan Rathore ,&nbsp;Satadru Chakraborty ,&nbsp;Swati Patankar ,&nbsp;Alla Gustchina ,&nbsp;Alexander Wlodawer ,&nbsp;Rickey Y. Yada ,&nbsp;Prasenjit Bhaumik","doi":"10.1016/j.crstbi.2024.100128","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100128","url":null,"abstract":"<div><p><em>Plasmodium</em> species are causative agents of malaria, a disease that is a serious global health concern. FDA-approved HIV-1 protease inhibitors (HIV-1 PIs) have been reported to be effective in reducing the infection by <em>Plasmodium</em> parasites in the population co-infected with both HIV-1 and malaria. However, the mechanism of HIV-1 PIs in mitigating <em>Plasmodium</em> pathogenesis during malaria/HIV-1 co-infection is not fully understood. In this study we demonstrate that HIV-1 drugs ritonavir (RTV) and lopinavir (LPV) exhibit the highest inhibition activity against plasmepsin II (PMII) and plasmepsin X (PMX) of <em>P. falciparum.</em> Crystal structures of the complexes of PMII with both drugs have been determined. The inhibitors interact with PMII <em>via</em> multiple hydrogen bonding and hydrophobic interactions. The P4 moiety of RTV forms additional interactions compared to LPV and exhibits conformational flexibility in a large S4 pocket of PMII. Our study is also the first to report inhibition of <em>P. falciparum</em> PMX by RTV and the mode of binding of the drug to the PMX active site. Analysis of the crystal structures implies that PMs can accommodate bulkier groups of these inhibitors in their S4 binding pockets. Structurally similar active sites of different vacuolar and non-vacuolar PMs suggest the potential of HIV-1 PIs in targeting these enzymes with differential affinities. Our structural investigations and biochemical data emphasize PMs as crucial targets for repurposing HIV-1 PIs as antimalarial drugs.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100128"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000059/pdfft?md5=38e95df2fe38c0df8f4ac91d7d0249de&pid=1-s2.0-S2665928X24000059-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139505362","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":"Living in trinity of extremes: Genomic and proteomic signatures of halophilic, thermophilic, and pH adaptation","authors":"Aidana Amangeldina ,&nbsp;Zhen Wah Tan ,&nbsp;Igor N. Berezovsky","doi":"10.1016/j.crstbi.2024.100129","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100129","url":null,"abstract":"<div><p>Since nucleic acids and proteins of unicellular prokaryotes are directly exposed to extreme environmental conditions, it is possible to explore the genomic-proteomic compositional determinants of molecular mechanisms of adaptation developed by them in response to harsh environmental conditions. Using a wealth of currently available complete genomes/proteomes we were able to explore signatures of adaptation to three environmental factors, pH, salinity, and temperature, observing major trends in compositions of their nucleic acids and proteins. We derived predictors of thermostability, halophilic, and pH adaptations and complemented them by the principal components analysis. We observed a clear difference between thermophilic and salinity/pH adaptations, whereas latter invoke seemingly overlapping mechanisms. The genome-proteome compositional trade-off reveals an intricate balance between the work of base paring and base stacking in stabilization of coding DNA and r/tRNAs, and, at the same time, universal requirements for the stability and foldability of proteins regardless of the nucleotide biases. Nevertheless, we still found hidden fingerprints of ancient evolutionary connections between the nucleotide and amino acid compositions indicating their emergence, mutual evolution, and adjustment. The evolutionary perspective on the adaptation mechanisms is further studied here by means of the comparative analysis of genomic/proteomic traits of archaeal and bacterial species. The overall picture of genomic/proteomic signals of adaptation obtained here provides a foundation for future engineering and design of functional biomolecules resistant to harsh environments.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100129"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000060/pdfft?md5=6db45050bbde9f78ac6d75eb6e876f66&pid=1-s2.0-S2665928X24000060-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139674781","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":"Guide to serial synchrotron crystallography","authors":"Ki Hyun Nam","doi":"10.1016/j.crstbi.2024.100131","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100131","url":null,"abstract":"<div><p>Serial crystallography (SX) is an emerging technique that can be used to determine the noncryogenic crystal structure of macromolecules while minimizing radiation damage. Applying SX using pump-probe or mix-and-inject techniques enables the observation of time-resolved molecular reactions and dynamics in macromolecules. After the successful demonstration of the SX experimental technique with structure determination in serial femtosecond crystallography using an X-ray free electron laser, this method was adapted to the synchrotron, leading to the development of serial synchrotron crystallography (SSX). SSX offers new opportunities for researchers to leverage SX techniques, contributing to the advancement of structural biology and offering a deeper understanding of the structure and function of macromolecules. This review covers the background and advantages of SSX and its experimental approach. It also discusses important considerations when conducting SSX experiments.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100131"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000084/pdfft?md5=c5f1d40127b05dcec44b6c96edc93911&pid=1-s2.0-S2665928X24000084-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139718264","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":"Soluble domains of cytochrome c-556 and Rieske iron–sulfur protein from Chlorobaculum tepidum: Crystal structures and interaction analysis","authors":"Hiraku Kishimoto ,&nbsp;Chihiro Azai ,&nbsp;Tomoya Yamamoto ,&nbsp;Risa Mutoh ,&nbsp;Tetsuko Nakaniwa ,&nbsp;Hideaki Tanaka ,&nbsp;Yohei Miyanoiri ,&nbsp;Genji Kurisu ,&nbsp;Hirozo Oh-oka","doi":"10.1016/j.crstbi.2023.100101","DOIUrl":"https://doi.org/10.1016/j.crstbi.2023.100101","url":null,"abstract":"<div><p>In photosynthetic green sulfur bacteria, the electron transfer reaction from menaquinol:cytochrome <em>c</em> oxidoreductase to the P840 reaction center (RC) complex occurs directly without any involvement of soluble electron carrier protein(s). X-ray crystallography has determined the three-dimensional structures of the soluble domains of the <em>CT0073</em> gene product and Rieske iron-sulfur protein (ISP). The former is a mono-heme cytochrome <em>c</em> with an α-absorption peak at 556 nm. The overall fold of the soluble domain of cytochrome <em>c</em>-556 (designated as cyt <em>c</em>-556_<em>sol</em>) consists of four α-helices and is very similar to that of water-soluble cyt <em>c</em>-554 that independently functions as an electron donor to the P840 RC complex. However, the latter's remarkably long and flexible loop between the α3 and α4 helices seems to make it impossible to be a substitute for the former. The structure of the soluble domain of the Rieske ISP (Rieske_<em>sol</em> protein) shows a typical β-sheets-dominated fold with a small cluster-binding and a large subdomain. The architecture of the Rieske_<em>sol</em> protein is bilobal and belongs to those of <em>b</em>₆<em>f</em>-type Rieske ISPs. Nuclear magnetic resonance (NMR) measurements revealed weak non-polar but specific interaction sites on Rieske_<em>sol</em> protein when mixed with cyt <em>c</em>-556_<em>sol</em>. Therefore, menaquinol:cytochrome <em>c</em> oxidoreductase in green sulfur bacteria features a Rieske/cyt<em>b</em> complex tightly associated with membrane-anchored cyt <em>c</em>-556.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"5 ","pages":"Article 100101"},"PeriodicalIF":2.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49813934","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":"Cryo-EM structure of the trehalose monomycolate transporter, MmpL3, reconstituted into peptidiscs","authors":"Julie Couston ,&nbsp;Zongxin Guo ,&nbsp;Kaituo Wang ,&nbsp;Pontus Gourdon ,&nbsp;Mickaël Blaise","doi":"10.1016/j.crstbi.2023.100109","DOIUrl":"https://doi.org/10.1016/j.crstbi.2023.100109","url":null,"abstract":"<div><p>Mycobacteria have an atypical thick and waxy cell wall. One of the major building blocks of such mycomembrane is trehalose monomycolate (TMM). TMM is a mycolic acid ester of trehalose that possesses long acyl chains with up to 90 carbon atoms. TMM represents an essential component of mycobacteria and is synthesized in the cytoplasm, and then flipped over the plasma membrane by a specific transporter known as MmpL3. Over the last decade, MmpL3 has emerged as an attractive drug target to combat mycobacterial infections. Recent three-dimensional structures of MmpL3 determined by X-ray crystallography and cryo-EM have increased our understanding of the TMM transport, and the mode of action of inhibiting compounds. These structures were obtained in the presence of detergent and/or in a lipidic environment. In this study, we demonstrate the possibility of obtaining a high-quality cryo-EM structure of MmpL3 without any presence of detergent through the reconstitution of the protein into peptidiscs. The structure was determined at an overall resolution of 3.2 Å and demonstrates that the overall structure of MmpL3 is preserved as compared to previous structures. Further, the study identified a new structural arrangement of the linker that fuses the two subdomains of the transmembrane domain, suggesting the feature may serve a role in the transport process.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"6 ","pages":"Article 100109"},"PeriodicalIF":2.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X23000156/pdfft?md5=30d57577920410fae3129100020f9753&pid=1-s2.0-S2665928X23000156-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134653072","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":"The conserved crown bridge loop at the catalytic centre of enzymes of the haloacid dehalogenase superfamily","authors":"David P. Leader,&nbsp;E. James Milner-White","doi":"10.1016/j.crstbi.2023.100105","DOIUrl":"10.1016/j.crstbi.2023.100105","url":null,"abstract":"<div><p>The crown bridge loop is hexapeptide motif in which the backbone carbonyl group at position 1 is hydrogen bonded to the backbone imino groups of positions 4 and 6. Residues at positions 1 and 4–6 are held in a tight substructure, but different orientations of the plane of the peptide bond between positions 2 and 3 result in two conformers: the 2,3-α_Rα_R crown bridge loop — found in approximately 7% of proteins — and the 2,3-β_Rα_L crown bridge loop, found in approximately 1–2% of proteins. We constructed a relational database in which we identified 60 instances of the 2,3-β_Rα_L conformer, and find that about half occur in enzymes of the haloacid dehalogenase (HAD) superfamily, where they are located next to the catalytic aspartate residue. Analysis of additional enzymes of the HAD superfamily in the extensive SCOPe dataset showed this crown bridge loop to be a conserved feature. Examination of available structures showed that the 2,3-β_Rα_L conformation — but not the 2,3-α_Rα_R conformation — allows the backbone carbonyl group at position 2 to interact with the essential Mg²⁺ ion. The possibility of interconversion between the 2,3-β_Rα_L and 2,3-α_Rα_R conformations during catalysis is discussed.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"6 ","pages":"Article 100105"},"PeriodicalIF":2.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/69/e8/main.PMC10541634.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41178270","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":"Local heterogeneity analysis of crystallographic and cryo-EM maps using shell-approximation","authors":"Vladimir Y. Lunin ,&nbsp;Natalia L. Lunina ,&nbsp;Alexandre G. Urzhumtsev","doi":"10.1016/j.crstbi.2023.100102","DOIUrl":"10.1016/j.crstbi.2023.100102","url":null,"abstract":"<div><p>In X-ray crystallography and cryo-EM, experimental maps can be heterogeneous, showing different level of details in different regions. In this work we interpret heterogeneity in terms of two parameters, assigned individually for each atom, combining the conventional atomic displacement parameter with the resolution of the atomic image in the map. We propose a local real-space procedure to estimate the values of these heterogeneity parameters, assuming that a fragment of the density map and atomic positions are given. The procedure is based on an analytic representation of the atomic image, as a function of the inhomogeneity parameters and atomic coordinates. In this article, we report the results of the tests both with maps simulated and those derived from experimental data. For simulated maps containing regions with different resolutions, the method determines the local map resolution around the atomic centers and the values of the displacement parameter with reasonable accuracy. For experimental maps, obtained as a Fourier synthesis of a given global resolution, estimated values of the local resolution are close to the global one, and the values of the estimated displacement parameters are close to the respective values of the closest atoms in the refined model. Shown successful applications of the proposed method to experimental crystallographic and cryo-EM maps can be seen as a practical proof of method.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"6 ","pages":"Article 100102"},"PeriodicalIF":2.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ff/50/main.PMC10329102.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9812483","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":"Structure of Helicobacter pylori dihydroneopterin aldolase suggests a fragment-based strategy for isozyme-specific inhibitor design","authors":"Gary X. Shaw ,&nbsp;Lixin Fan ,&nbsp;Scott Cherry ,&nbsp;Genbin Shi ,&nbsp;Joseph E. Tropea ,&nbsp;Xinhua Ji","doi":"10.1016/j.crstbi.2023.100095","DOIUrl":"https://doi.org/10.1016/j.crstbi.2023.100095","url":null,"abstract":"<div><p>Dihydroneopterin aldolase (DHNA) is essential for folate biosynthesis in microorganisms. Without a counterpart in mammals, DHNA is an attractive target for antimicrobial agents. <em>Helicobacter pylori</em> infection occurs in human stomach of over 50% of the world population, but first-line therapies for the infection are facing rapidly increasing resistance. Novel antibiotics are urgently needed, toward which structural information on potential targets is critical. We have determined the crystal structure of <em>H. pylori</em> DHNA (HpDHNA) in complex with a pterin molecule (HpDHNA:Pterin) at 1.49-Å resolution. The HpDHNA:Pterin complex forms a tetramer in crystal. The tetramer is also observed in solution by dynamic light scattering and confirmed by small-angle X-ray scattering. To date, all but one reported DHNA structures are octameric complexes. As the only exception, ligand-free <em>Mycobacterium tuberculosis</em> DHNA (apo-MtDHNA) forms a tetramer in crystal, but its active sites are only partially formed. In contrast, the tetrameric HpDHNA:Pterin complex has well-formed active sites. Each active site accommodates one pterin molecule, but the exit of active site is blocked by two amino acid residues exhibiting a contact distance of 5.2 ​Å. In contrast, the corresponding contact distance in <em>Staphylococcus aureus</em> DHNA (SaDHNA) is twice the size, ranging from 9.8 to 10.5 ​Å, for ligand-free enzyme, the substrate complex, the product complex, and an inhibitor complex. This large contact distance indicates that the active site of SaDHNA is wide open. We propose that this isozyme-specific contact distance (ISCD) is a characteristic feature of DHNA active site. Comparative analysis of HpDHNA and SaDHNA structures suggests a fragment-based strategy for the development of isozyme-specific inhibitors.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"5 ","pages":"Article 100095"},"PeriodicalIF":2.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49773028","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}