Article
- The EMBO Journal (2006) 25, 5026 - 5035
- doi:10.1038/sj.emboj.7601358
Published online: 28 September 2006
Subject Category:
Restraining the conformation of HIV-1 gp120 by removing a flexible loop
Sophia Rits-Volloch1,2,a, Gary Frey3,a, Stephen C Harrison1,2,3 and Bing Chen1
- Laboratory of Molecular Medicine, The Children's Hospital, Boston, MA, USA
- Howard Hughes Medical Institute, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
Correspondence to:
Bing Chen, Laboratory of Molecular Medicine, Enders 670, Children's Hospital, 320 Longwood Avenue, Boston, MA 02115, USA. Tel.: +1 617 355 625; Fax: +1 617 730 1967; E-mail: bchen@crystal.harvard.edu
aThese authors contributed equally to this work
Received 29 June 2006; Accepted 29 August 2006
Abstract
The trimeric HIV/SIV envelope glycoprotein, gp160, is cleaved to noncovalently associated fragments, gp120 and gp41. Binding of gp120 to viral receptors leads to large structural rearrangements in both fragments. The unliganded gp120 core has a disordered 
3–5 loop, which reconfigures upon CD4 binding into an ordered, extended strand. Molecular modeling suggests that residues in this loop may contact gp41. We show here that deletions in the 3–5 loop of HIV-1 gp120 weaken the binding of CD4 and prevent formation of the epitope for monoclonal antibody (mAb) 17b (which recognizes the coreceptor site). Formation of an encounter complex with CD4 binding and interactions of gp120 with mAbs b12 and 2G12 are not affected by these deletions. Thus, deleting the 3–5 loop blocks the gp120 conformational change and may offer a strategy for design of restrained immunogens. Moreover, mutations in the SIV 3–5 loop lead to greater spontaneous dissociation of gp120 from cell-associated trimers. We suggest that the CD4-induced rearrangement of this loop releases structural constraints on gp41 and thus potentiates its fusion activity.
Keywords:
- CD4,
- envelope,
- gp120,
- HIV
