Herschhorn, AlonGu, ChristopherMoraca, FrancescaMa, XiaochuFarrell, MarkSmith, Amos B.Pancera, MarieKwong, Peter D.Schön, ArneFreire, ErnestoAbrams, CameronBlanchard, Scott C.Mothes, WaltherSodroski, Joseph2017-12-062017Herschhorn, A., C. Gu, F. Moraca, X. Ma, M. Farrell, A. B. Smith, M. Pancera, et al. 2017. “The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions.” Nature Communications 8 (1): 1049. doi:10.1038/s41467-017-01119-w. http://dx.doi.org/10.1038/s41467-017-01119-w.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492417The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally “closed” State 1 to more “open” conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements. We identify the gp120 β20–β21 element as a major regulator of Env transitions. Several amino acid changes in the β20–β21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding. These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. These data provide insights into the molecular mechanism and vulnerability of HIV-1 entry.en-USJournal Article2017-12-0610.1038/s41467-017-01119-w