Current Research in Structural Biology最新文献

{"title":"Regulation of the interactions between human eIF5 and eIF1A by the CK2 kinase","authors":"Nathan Gamble,&nbsp;Eleanor Elise Paul,&nbsp;Bibin Anand,&nbsp;Assen Marintchev","doi":"10.1016/j.crstbi.2022.09.003","DOIUrl":"10.1016/j.crstbi.2022.09.003","url":null,"abstract":"<div><p>Translation initiation in eukaryotes relies on a complex network of interactions that are continuously reorganized throughout the process. As more information becomes available about the structure of the ribosomal preinitiation complex (PIC) at various points in translation initiation, new questions arise about which interactions occur when, their roles, and regulation. The eukaryotic translation factor (eIF) 5 is the GTPase-activating protein (GAP) for the GTPase eIF2, which brings the initiator Met-tRNA_i to the PIC. eIF5 also plays a central role in PIC assembly and remodeling through interactions with other proteins, including eIFs 1, 1A, and 3c. Phosphorylation by casein kinase 2 (CK2) significantly increases the eIF5 affinity for eIF2. The interaction between eIF5 and eIF1A was reported to be mediated by the eIF5 C-terminal domain (CTD) and the eIF1A N-terminal tail. Here, we report a new contact interface, between eIF5-CTD and the oligonucleotide/oligosaccharide-binding fold (OB) domain of eIF1A, which contributes to the overall affinity between the two proteins. We also show that the interaction is modulated by dynamic intramolecular interactions within both eIF5 and eIF1A. CK2 phosphorylation of eIF5 increases its affinity for eIF1A, offering new insights into the mechanisms by which CK2 stimulates protein synthesis and cell proliferation.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 308-319"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/79/5b/main.PMC9508154.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9578516","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":"Biochemical and structural analysis of a cytosolic sulfotransferase of the malaria vector Anopheles gambiae overexpressed in the reproductive tissues","authors":"Arianna Esposito Verza ,&nbsp;Riccardo Miggiano ,&nbsp;Fabrizio Lombardo ,&nbsp;Carmine Fiorillo ,&nbsp;Bruno Arcà ,&nbsp;Beatrice Purghé ,&nbsp;Erika Del Grosso ,&nbsp;Ubaldina Galli ,&nbsp;Menico Rizzi ,&nbsp;Franca Rossi","doi":"10.1016/j.crstbi.2022.07.001","DOIUrl":"10.1016/j.crstbi.2022.07.001","url":null,"abstract":"<div><p>The temporary or permanent chemical modification of biomolecules is a crucial aspect in the physiology of all living species. However, while some modules are well characterised also in insects, others did not receive the same attention. This holds true for sulfo-conjugation that is catalysed by cytosolic sulfotransferases (SULT), a central component of the metabolism of endogenous low molecular weight molecules and xenobiotics. In particular, limited information is available about the functional roles of the mosquito predicted enzymes annotated as SULTs in genomic databases. The herein described research is the first example of a biochemical and structural study of a SULT of a mosquito species, in general, and of the malaria vector <em>Anopheles gambiae</em> in particular. We confirmed that the AGAP001425 transcript displays a peculiar expression pattern that is suggestive of a possible involvement in modulating the mosquito reproductive tissues physiology, a fact that could raise attention on the enzyme as a potential target for insect-containment strategies. The crystal structures of the enzyme in alternative ligand-bound states revealed elements distinguishing <em>Ag</em>SULT-001425 from other characterized SULTs, including a peculiar conformational plasticity of a discrete region that shields the catalytic cleft and that could play a main role in the dynamics of the reaction and in the substrate selectivity of the enzyme. Along with further <em>in vitro</em> biochemical studies, our structural investigations could provide a framework for the discovery of small-molecule inhibitors to assess the effect of interfering with <em>Ag</em>SULT-001425-mediated catalysis at the organismal level.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 246-255"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e8/73/main.PMC9356239.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704012","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":"FOXO transcription factors differ in their dynamics and intra/intermolecular interactions","authors":"Emil Spreitzer ,&nbsp;T. Reid Alderson ,&nbsp;Benjamin Bourgeois ,&nbsp;Loretta Eggenreich ,&nbsp;Hermann Habacher ,&nbsp;Greta Bramerdorfer ,&nbsp;Iva Pritišanac ,&nbsp;Pedro A. Sánchez-Murcia ,&nbsp;Tobias Madl","doi":"10.1016/j.crstbi.2022.04.001","DOIUrl":"10.1016/j.crstbi.2022.04.001","url":null,"abstract":"<div><p>Transcription factors play key roles in orchestrating a plethora of cellular mechanisms and controlling cellular homeostasis. Transcription factors share distinct DNA binding domains, which allows to group them into protein families. Among them, the Forkhead box O (FOXO) family contains transcription factors crucial for cellular homeostasis, longevity and response to stress. The dysregulation of FOXO signaling is linked to drug resistance in cancer therapy or cellular senescence, however, selective drugs targeting FOXOs are limited, thus knowledge about structure and dynamics of FOXO proteins is essential. Here, we provide an extensive study of structure and dynamics of all FOXO family members. We identify residues accounting for different dynamic and structural features. Furthermore, we show that the auto-inhibition of FOXO proteins by their C-terminal trans-activation domain is conserved throughout the family and that these interactions are not only possible intra-, but also inter-molecularly. This indicates a model in which FOXO transcription factors would modulate their activities by interacting mutually.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 118-133"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X22000095/pdfft?md5=2c2ec2f297b19f624c1eda55d104f5c9&pid=1-s2.0-S2665928X22000095-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47295491","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 sulfoquinovosyl glycerol binding protein SmoF binds and accommodates plant sulfolipids","authors":"Alexander J.D. Snow ,&nbsp;Mahima Sharma ,&nbsp;James P. Lingford ,&nbsp;Yunyang Zhang ,&nbsp;Janice W.-Y. Mui ,&nbsp;Ruwan Epa ,&nbsp;Ethan D. Goddard-Borger ,&nbsp;Spencer J. Williams ,&nbsp;Gideon J. Davies","doi":"10.1016/j.crstbi.2022.03.001","DOIUrl":"10.1016/j.crstbi.2022.03.001","url":null,"abstract":"<div><p>Sulfoquinovose (SQ) is the anionic headgroup of the ubiquitous plant sulfolipid, sulfoquinovosyl diacylglycerol (SQDG). SQDG can undergo delipidation to give sulfoquinovosyl glycerol (SQGro) and further glycoside cleavage to give SQ, which can be metabolized through microbial sulfoglycolytic pathways. Exogenous SQDG metabolites are imported into bacteria through membrane spanning transporter proteins. The recently discovered sulfoglycolytic sulfoquinovose monooxygenase (sulfo-SMO) pathway in <em>Agrobacterium tumefaciens</em> features a periplasmic sulfoquinovosyl glycerol binding protein, SmoF, and an ATP-binding cassette (ABC) transporter. Here, we use X-ray crystallography, differential scanning fluorimetry and isothermal titration calorimetry to study SQ glycoside recognition by SmoF. This work reveals that in addition to SQGro, SmoF can also bind SQ, a simple methyl glycoside and even a short-chain SQDG analogue. Molecular recognition of these substrates is achieved through conserved interactions with the SQ-headgroup together with more plastic interactions with the aglycones. This suggests that the solute binding protein of <em>A. tumefaciens,</em> and related SQ-binding proteins from other sulfoglycolytic pathways, can provide their host organisms direct access to most of the SQ metabolites known to be produced by phototrophs.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 51-58"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X22000058/pdfft?md5=92ea91c60cc0a0fabd078c308ccda613&pid=1-s2.0-S2665928X22000058-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44773542","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":"Transactivation domain of Adenovirus Early Region 1A (E1A): Investigating folding dynamics and aggregation","authors":"Nitin Sharma ,&nbsp;Kundlik Gadhave ,&nbsp;Prateek Kumar ,&nbsp;Rajanish Giri","doi":"10.1016/j.crstbi.2022.01.001","DOIUrl":"10.1016/j.crstbi.2022.01.001","url":null,"abstract":"<div><p>Transactivation domain of Adenovirus Early region 1A (E1A) oncoprotein is an intrinsically disordered molecular hub protein. It is involved in binding to different domains of human cell transcriptional co-activators such as retinoblastoma (pRb), CREB-binding protein (CBP), and its paralogue p300. The conserved region 1 (TAD) of E1A is known to undergo structural transitions and folds upon interaction with transcriptional adaptor zinc finger 2 (TAZ2). Previous reports on Taz2-E1A studies have suggested the formation of helical conformations of E1A-TAD. However, the folding behavior of the TAD region in isolation has not been studied in detail. Here, we have elucidated the folding behavior of E1A peptide at varied temperatures and solution conditions. Further, we have studied the effects of macromolecular crowding on E1A-TAD peptide. Additionally, we have also predicted the molecular recognition features of E1A using MoRF predictors. The predicted MoRFs are consistent with its structural transitions observed during TAZ2 interactions for transcriptional regulation in literature. Also, as a general rule of MoRFs, E1A undergoes helical transitions in alcohol and osmolyte solution. Finally, we studied the aggregation behavior of E1A, where we observed that the E1A could form amyloid-like aggregates that are cytotoxic to mammalian cells.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 29-40"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/da/77/main.PMC8801969.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39908538","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":"HGDiscovery: An online tool providing functional and phenotypic information on novel variants of homogentisate 1,2- dioxigenase","authors":"Malancha Karmakar ,&nbsp;Vittoria Cicaloni ,&nbsp;Carlos H.M. Rodrigues ,&nbsp;Ottavia Spiga ,&nbsp;Annalisa Santucci ,&nbsp;David B. Ascher","doi":"10.1016/j.crstbi.2022.08.001","DOIUrl":"10.1016/j.crstbi.2022.08.001","url":null,"abstract":"<div><p>Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in the body. Affected individuals lack functional levels of an enzyme required to breakdown HGA. Mutations in the homogentisate 1,2-dioxygenase (HGD) gene cause AKU and they are responsible for deficient levels of functional HGD, which, in turn, leads to excess levels of HGA. Although HGA is rapidly cleared from the body by the kidneys, in the long term it starts accumulating in various tissues, especially cartilage. Over time (rarely before adulthood), it eventually changes the color of affected tissue to slate blue or black. Here we report a comprehensive mutation analysis of 111 pathogenic and 190 non-pathogenic HGD missense mutations using protein structural information. Using our comprehensive suite of graph-based signature methods, mCSM complemented with sequence-based tools, we studied the functional and molecular consequences of each mutation on protein stability, interaction and evolutionary conservation. The scores generated from the structure and sequence-based tools were used to train a supervised machine learning algorithm with 89% accuracy. The empirical classifier was used to generate the variant phenotype for novel HGD missense mutations. All this information is deployed as a user friendly freely available web server called HGDiscovery (<span>https://biosig.lab.uq.edu.au/hgdiscovery/</span><svg><path></path></svg>).</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 271-277"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9471331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40367389","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":"Integrative structural studies of the SARS-CoV-2 spike protein during the fusion process (2022)","authors":"Jacob C. Miner ,&nbsp;Paul W. Fenimore ,&nbsp;William M. Fischer ,&nbsp;Benjamin H. McMahon ,&nbsp;Karissa Y. Sanbonmatsu ,&nbsp;Chang-Shung Tung","doi":"10.1016/j.crstbi.2022.06.004","DOIUrl":"10.1016/j.crstbi.2022.06.004","url":null,"abstract":"<div><p>SARS-CoV-2 is the virus responsible for the COVID-19 pandemic and catastrophic, worldwide health and economic impacts. The spike protein on the viral surface is responsible for viral entry into the host cell<del>.</del> The binding of spike protein to the host cell receptor ACE2 is the first step leading to fusion of the host and viral membranes. Despite the vast amount of structure data that has been generated for the spike protein of SARS-CoV-2, many of the detailed structures of the spike protein in different stages of the fusion pathway are unknown, leaving a wealth of potential drug-target space unexplored. The atomic-scale structure of the complete S2 segment, as well as the complete fusion intermediate are also unknown and represent major gaps in our knowledge of the infectious pathway of SAR-CoV-2. The conformational changes of the spike protein during this process are similarly not well understood. Here we present structures of the spike protein at different stages of the fusion process. With the transitions being a necessary step before the receptor binding, we propose sites along the transition pathways as potential targets for drug development.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 220-230"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/20/50/main.PMC9221923.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40407521","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":"Fragment-based exploration of the 14-3-3/Amot-p130 interface","authors":"Federica Centorrino,&nbsp;Blaž Andlovic,&nbsp;Peter Cossar,&nbsp;Luc Brunsveld,&nbsp;Christian Ottmann","doi":"10.1016/j.crstbi.2021.12.003","DOIUrl":"10.1016/j.crstbi.2021.12.003","url":null,"abstract":"<div><p>The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as ‘<em>undruggable’</em> targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the ‘<em>tractability’</em> of the desired protein target has seen a remarkable development in recent years. In this study, we explore the molecular characteristics of the 14-3-3/Amot-p130 PPI and the conceptual possibility of targeting this interface using X-ray crystallography fragment-based screening. We report the first structural elucidation of the 14-3-3 binding motif of Amot-p130 and the characterization of the binding mode and affinities involved. We made use of fragments to probe the ‘<em>ligandability’</em> of the 14-3-3/Amot-p130 composite binding pocket. Here we disclose initial hits with promising stabilizing activity and an early-stage selectivity toward the Amot-p130 motifs over other representatives 14-3-3 partners. Our findings highlight the potential of using fragments to characterize and explore proteins' surfaces and might provide a starting point toward the development of small molecules capable of acting as <em>molecular glues</em>.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 21-28"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5e/bc/main.PMC8743172.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39826584","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":"Nonexponential kinetics captured in sequential unfolding of polyproteins over a range of loads","authors":"Einat Chetrit ,&nbsp;Sabita Sharma ,&nbsp;Uri Maayan ,&nbsp;Maya Georgia Pelah ,&nbsp;Ziv Klausner ,&nbsp;Ionel Popa ,&nbsp;Ronen Berkovich","doi":"10.1016/j.crstbi.2022.04.003","DOIUrl":"10.1016/j.crstbi.2022.04.003","url":null,"abstract":"<div><p>While performing under mechanical loads <em>in vivo</em>, polyproteins are vitally involved in cellular mechanisms such as regulation of tissue elasticity and mechano-transduction by unfolding their comprising domains and extending them. It is widely thought that the process of sequential unfolding of polyproteins follows an exponential kinetics as the individual unfolding events exhibit identical and identically distributed (iid) Poisson behavior. However, it was shown that under high loads, the sequential unfolding kinetics displays nonexponential kinetics that alludes to aging by a subdiffusion process. Statistical order analysis of this kinetics indicated that the individual unfolding events are not iid, and cannot be defined as a Poisson (memoryless) process. Based on numerical simulations it was argued that this behavior becomes less pronounced with lowering the load, therefore it is to be expected that polyproteins unfolding under lower forces will follow a Poisson behavior. This expectation serves as the motivation of the current study, in which we investigate the effect of force lowering on the unfolding kinetics of Poly-L₈ under varying loads, specifically high (150, 100 ​pN) and moderate-low (45, 30, 20 ​pN) forces. We found that a hierarchy among the unfolding events still exists even under low loads, again resulting in nonexponential behavior. We observe that analyzing the dwell-time distributions with stretched-exponentials and power laws give rise to different phenomenological trends. Using statistical order analysis, we demonstrated that even under the lowest load, the sequential unfolding cannot be considered as iid, in accord with the power law distribution. Additional free energy analysis revealed the contribution of the unfolded segments elasticity that scales with the force on the overall one-dimensional contour of the energy landscape, but more importantly, it discloses the hierarchy within the activation barriers during sequential unfolding that account for the observed nonexponentiality.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 106-117"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X22000113/pdfft?md5=34c74cdfdd79fbd9202a5be67013bd05&pid=1-s2.0-S2665928X22000113-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45431399","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":"Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneity","authors":"Ghoncheh Mashayekhi ,&nbsp;John Vant ,&nbsp;Abhigna Polavarapu ,&nbsp;Abbas Ourmazd ,&nbsp;Abhishek Singharoy","doi":"10.1016/j.crstbi.2022.02.001","DOIUrl":"10.1016/j.crstbi.2022.02.001","url":null,"abstract":"<div><p>Cryo-electron microscopy (cryo-EM) has produced a number of structural models of the SARS-CoV-2 spike, already prompting biomedical outcomes. However, these reported models and their associated electrostatic potential maps represent an unknown admixture of conformations stemming from the underlying energy landscape of the spike protein. As with any protein, some of the spike's conformational motions are expected to be biophysically relevant, but cannot be interpreted only by static models. Using experimental cryo-EM images, we present the energy landscape of the glycosylated spike protein, and identify the diversity of low-energy conformations in the vicinity of its open (so called 1RBD-up) state. The resulting atomic refinement reveal global and local molecular rearrangements that cannot be inferred from an average 1RBD-up cryo-EM model. Here we report varied degrees of “openness” in global conformations of the 1RBD-up state, not revealed in the single-model interpretations of the density maps, together with conformations that overlap with the reported models. We discover how the glycan shield contributes to the stability of these low-energy conformations. Five out of six binding sites we analyzed, including those for engaging ACE2, therapeutic mini-proteins, linoleic acid, two different kinds of antibodies, switch conformations between their known apo- and holo-conformations, even when the global spike conformation is 1RBD-up. This apo-to-holo switching is reminiscent of a conformational preequilibrium. We found only one binding site, namely that of AB-C135 remains in apo state within all the sampled free energy-minimizing models, suggesting an induced fit mechanism for the docking of this antibody to the spike.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"4 ","pages":"Pages 68-77"},"PeriodicalIF":2.8,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4f/91/main.PMC8902891.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10487902","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}