The structure of an HIV-1 specific cell entry inhibitor in complex with the HIV-1 gp41 trimeric core.
The three-dimensional structure of the complex between an HIV-1 cell-entry inhibitor selected from screening a combinatorial library of non-natural building blocks and the central, trimeric, coiled-coil core of HIV-1 gp41 has been determined by X-ray crystallography. The biased combinatorial library was designed to identify ligands binding in nonpolar pockets on the surface of the coiled-coil core of gp41. The crystal structure shows that the non-peptide moiety of the inhibitor binds to the targeted cavity in two different binding modes. This result suggests a strategy for increasing inhibitor potency by use of a second-generation combinatorial library designed to give simultaneous occupancy of both binding sites.
Zhou
G
G
Laboratory of Molecular Medicine, The Children's Hospital, Boston, MA 02115, USA.
Ferrer
M
M
Chopra
R
R
Kapoor
T M
TM
Strassmaier
T
T
Weissenhorn
W
W
Skehel
J J
JJ
Oprian
D
D
Schreiber
S L
SL
Harrison
S C
SC
Wiley
D C
DC
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D008024:Ligands; D010455:Peptides