L565M mutation in HIV-1 glycoprotein 41 stabilizes the coiled-coil structure.
N-terminal and C-terminal heptad repeats (NHR and CHR) of HIV type 1 (HIV-1) glycoprotein 41 are known to be regions directly related to cell fusion during virus attack, and their complex core constructs a coiled-coil structure in the fusion process. In our recent studies, MT-4/17-3-6, a strain of HIV-1, showed the strong resistance to peptide fusion inhibitors compared with other strains such as MT-4/LAI, L-2 and CU98-26, and had a distinctive L565M mutation in the central region of NHR. To investigate the relationship between the mutation and resistance, we performed a molecular modeling of the coiled-coil of MT-4/17-3-6 by using energy minimization and molecular dynamics simulation based on the MT-4/LAI X-ray structure. As a result, we found that H564 in the NHR was pushed to the outer side by this mutation, and three hydrogen bond bridges of Y638-H564-E560-Q650 could be formed, enclosing the coiled-coil. The binding of peptide inhibitors would be disturbed by the structural stabilization of these bridges in MT-4/17-3-6.
Yamamoto
Daisuke
D
Biomedical Computation Center, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan. center@art.osaka-med.ac.jp
Li
Gui-Mei
GM
Ikuta
Kazuyoshi
K
Goto
Toshiyuki
T
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D018360:Crystallography, X-Ray; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics*; D015497:HIV-1 / Q000737:chemistry* / Q000235:genetics*; D006860:Hydrogen Bonding; D008239:Lysine / Q000235:genetics* / Q000378:metabolism; D008715:Methionine / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary
D015700:HIV Envelope Protein gp41; D008715:Methionine; D008239:Lysine