Distinct conformational states of SARS-CoV-2 spike protein
Yongfei Cai,Yongfei Cai,Jun Zhang,Jun Zhang,Tianshu Xiao,Tianshu Xiao,Hanqin Peng,Sarah M. Sterling,Richard M. Walsh,Shaun Rawson,Sophia Rits-Volloch,Bing Chen,Bing Chen +12 more
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TLDR
Two cryo–electron microscopy structures derived from a preparation of the full-length S protein, representing its prefusion and postfusion conformations, are reported, advancing the understanding of SARS-CoV-2 entry and may guide the development of vaccines and therapeutics.Abstract:
Intervention strategies are urgently needed to control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The trimeric viral spike (S) protein catalyzes fusion between viral and target cell membranes to initiate infection. Here, we report two cryo-electron microscopy structures derived from a preparation of the full-length S protein, representing its prefusion (2.9-angstrom resolution) and postfusion (3.0-angstrom resolution) conformations, respectively. The spontaneous transition to the postfusion state is independent of target cells. The prefusion trimer has three receptor-binding domains clamped down by a segment adjacent to the fusion peptide. The postfusion structure is strategically decorated by N-linked glycans, suggesting possible protective roles against host immune responses and harsh external conditions. These findings advance our understanding of SARS-CoV-2 entry and may guide the development of vaccines and therapeutics.read more
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Platycodin D, a natural component of Platycodon grandiflorum, prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection by hindering membrane fusion.
Tai Young Kim,Sangeun Jeon,Young-Ho Jang,Lizaveta Gotina,Lizaveta Gotina,Joungha Won,Yeon Ha Ju,Sunpil Kim,Minwoo Wendy Jang,Woojin Won,Mingu Gordon Park,Ae Nim Pae,Ae Nim Pae,Sunkyu Han,Seungtaek Kim,C. Justin Lee +15 more
TL;DR: Platycodin D (PD) is a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry.
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Elucidation of interactions regulating conformational stability and dynamics of SARS-CoV-2 S-protein.
TL;DR: In this article, the authors performed all-atom molecular dynamics simulations of both down and up forms of a fully glycosylated S-protein in solution as well as targeted molecular dynamics simulation between them to elucidate key interdomain interactions for stabilizing each form and inducing the large-scale conformational transitions.
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Development and Validation of a Multiplex, Bead-Based Assay to Detect Antibodies Directed Against SARS-CoV-2 Proteins.
Robert A. Bray,Jar How Lee,Peter Brescia,Deepali Kumar,Thoa Nong,Remi Shih,E. Steve Woodle,Jonathan S. Maltzman,Jonathan S. Maltzman,Howard M. Gebel +9 more
TL;DR: This new assay provides a novel tool to interrogate the spectrum of immune responses to SAR-CoV-2 and is uniquely suitable for use in the transplant setting.
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An ultra-high affinity synthetic nanobody blocks SARS-CoV-2 infection by locking Spike into an inactive conformation
Michael Schoof,Bryan Faust,R.A. Saunders,Smriti Sangwan,Veronica V. Rezelj,Nick Hoppe,Nick Hoppe,Morgane Boone,Christian Billesboelle,Christian Billesboelle,Cristina Puchades,Caleigh M. Azumaya,Caleigh M. Azumaya,Huong T. Kratochvil,M. Zimanyi,Ishan Deshpande,Ishan Deshpande,Jiahao Liang,S. Dickinson,Henry C. Nguyen,Cynthia M. Chio,Gregory E Merz,Michael C. Thompson,Michael C. Thompson,Devan Diwanji,Devan Diwanji,Kaitlin Schaefer,Aditya A. Anand,Niv Dobzinski,Beth S. Zha,Camille R. Simoneau,Camille R. Simoneau,Kristoffer E. Leon,Kristoffer E. Leon,Kris M. White,Un Seng Chio,Un Seng Chio,Meghna Gupta,Mingliang Jin,Fei Li,Yanxin Liu,Kaihua Zhang,David Bulkley,Ming Sun,Amber M. Smith,Alexandrea N. Rizo,Frank R. Moss,Axel F. Brilot,Sergei Pourmal,Raphael Trenker,Thomas H. Pospiech,Sayan Gupta,Benjamin Barsi-Rhyne,Vladislav Belyy,A.W. Barile-Hill,Silke Nock,Yuwei Liu,Nevan J. Krogan,Corie Y. Ralston,Danielle L. Swaney,Adolfo García-Sastre,Melanie Ott,Melanie Ott,Marco Vignuzzi,Peter Walter,Aashish Manglik +65 more
TL;DR: Single-domain antibodies (nanobodies) are developed that potently disrupt the interaction between the SARS-CoV-2 Spike and ACE2, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.
Journal ArticleDOI
Free Energy Landscapes from SARS-CoV-2 Spike Glycoprotein Simulations Suggest that RBD Opening Can Be Modulated via Interactions in an Allosteric Pocket.
Lucy Fallon,Kellon A.A. Belfon,Lauren Raguette,Yuzhang Wang,Darya Stepanenko,Abbigayle Cuomo,Jose Guerra,Stephanie Budhan,Sarah Varghese,Christopher P Corbo,Robert C. Rizzo,Carlos Simmerling +11 more
TL;DR: In this article, the free energy landscape for RBD opening and interactions in an allosteric pocket that influence RBD dynamics were mapped and identified, and small molecules that modulate the RBD equilibrium were used as experimental probes to quantify RBD conformational heterogeneity.
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