Conformational rearrangements required of the V3 loop of HIV-1 gp120 for proteolytic cleavage and infection.
HIV gp120 is specifically cleaved at a single site in the V3 loop between Arg315 and Ala316 by thrombin. Previous observations by others have indicated that binding to CD4 enhances the rate of V3 loop cleavage, and that this cleavage is a prerequisite for HIV infection. Other observations also suggest that the cleavage site is in a type II beta-turn centered at Pro313-Gly314. However, our docking experiments indicate that this conformation cannot dock to thrombin and other trypsin-like serine proteases. Thus, based on the thrombin-bound conformation of peptide substrates, we propose that CD4 binding, at a site remote from the V3 loop, induces and stabilizes a trans to cis isomerization of the highly conserved residue Pro313, and that this conformational shift is a prerequisite for cleavage by a 'thrombin-like' cellular protease and subsequent infection.
Johnson
M E
ME
Center for Pharmaceutical Biotechnology, University of Illinois at Chicago 60612-7230.
Lin
Z
Z
Padmanabhan
K
K
Tulinsky
A
A
Kahn
M
M
D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry* / Q000472:pathogenicity*; D006860:Hydrogen Bonding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013917:Thrombin / Q000378:metabolism*
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D013917:Thrombin; D015951:Factor Xa