Scharf, Louise and Wang, Haoqing and Gao, Han and Chen, Songye and McDowall, Alasdair W. and Bjorkman, Pamela J. (2015) Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env. Cell, 162 (6). pp. 1379-1390. ISSN 0092-8674. PMCID PMC4587768. http://resolver.caltech.edu/CaltechAUTHORS:20150911-094720986
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The HIV-1 envelope (Env) spike contains limited epitopes for broadly neutralizing antibodies (bNAbs); thus, most neutralizing antibodies are strain specific. The 8ANC195 epitope, defined by crystal and electron microscopy (EM) structures of bNAb 8ANC195 complexed with monomeric gp120 and trimeric Env, respectively, spans the gp120 and gp41 Env subunits. To investigate 8ANC195’s gp41 epitope at higher resolution, we solved a 3.58 Å crystal structure of 8ANC195 complexed with fully glycosylated Env trimer, revealing 8ANC195 insertion into a glycan shield gap to contact gp120 and gp41 glycans and protein residues. To determine whether 8ANC195 recognizes the CD4-bound open Env conformation that leads to co-receptor binding and fusion, one of several known conformations of virion-associated Env, we solved EM structures of an Env/CD4/CD4-induced antibody/8ANC195 complex. 8ANC195 binding partially closed the CD4-bound trimer, confirming structural plasticity of Env by revealing a previously unseen conformation. 8ANC195’s ability to bind different Env conformations suggests advantages for potential therapeutic applications.
|Additional Information:||© 2015 Elsevier. Received: May 3, 2015. Revised: June 19, 2015. Accepted: July 28, 2015. Published: September 10, 2015. This research was supported by the National Institute Of Allergy and Infectious Diseases of the National Institutes of Health Grant HIVRAD P01 AI100148 (P.J.B.) (the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health), the Bill and Melinda Gates Foundation (Collaboration for AIDS Vaccine Discovery Grant 1040753 [P.J.B.]), the National Institutes of Health Grant 2 P50 GM082545-06 (P.J.B.), the American Cancer Society Grant PF-13-076-01-MPC (L.S.), and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech that helped support electron microscopy; Grant Jensen for advice and support for EM; Jost Vielmetter and the Caltech Protein Expression Center for producing proteins and use of the Biacore T200; Priyanthi Gnanapragasam and René Mares for performing neutralization assays; the beamline staff at the Advanced Photon Source GM/CA-CAT for use and support for beamline 23ID-D; Marta Murphy and Rachel Galimidi for assistance with figures; and Michel Nussenzweig, Johannes Scheid, and Anthony West for helpful discussions and critical reading of the manuscript. Author Contributions: L.S. prepared samples for structural studies, solved and analyzed crystal structure, performed and analyzed binding studies, and analyzed neutralization and Ab mutant data; H.W., L.S., S.C. and A.W.M. collected EM data; H.W. and L.S. solved and analyzed EM structures; H.G. expressed and purified proteins; L.S., H.W., and P.J.B. analyzed data and wrote the manuscript. Accession Numbers: Crystallographic atomic coordinates and structure factors were deposited in the Protein Data Bank under accession code PDB: 5CJX. EM reconstructions were deposited in the Electron Microscopy Data Bank under accession codes EMD: 3086 and EMD: 3096.|
|PubMed Central ID:||PMC4587768|
|Official Citation:||Louise Scharf, Haoqing Wang, Han Gao, Songye Chen, Alasdair W. McDowall, Pamela J. Bjorkman, Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env, Cell, Volume 162, Issue 6, 10 September 2015, Pages 1379-1390, ISSN 0092-8674, http://dx.doi.org/10.1016/j.cell.2015.08.035. (http://www.sciencedirect.com/science/article/pii/S0092867415010879)|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||George Porter|
|Deposited On:||11 Sep 2015 17:10|
|Last Modified:||07 Mar 2016 16:13|
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