期刊
EMBO JOURNAL
卷 25, 期 20, 页码 5026-5035出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601358
关键词
CD4; envelope; gp120; HIV
资金
- NIAID NIH HHS [AI-67854, U01 AI067854, U19 AI067854] Funding Source: Medline
- NIGMS NIH HHS [R01 GM075752, GM-75752] Funding Source: Medline
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 beta 3-beta 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 beta 3-beta 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 beta 3-beta 5 loop blocks the gp120 conformational change and may offer a strategy for design of restrained immunogens. Moreover, mutations in the SIV beta 3-beta 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.
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