1C6Z

ALTERNATE BINDING SITE FOR THE P1-P3 GROUP OF A CLASS OF POTENT HIV-1 PROTEASE INHIBITORS AS A RESULT OF CONCERTED STRUCTURAL CHANGE IN 80'S LOOP.

Summary for 1C6Z

• Entry DOI: 10.2210/pdb1c6z/pdb
• Related: 1c6x 1c6y 1c70
• Related PRD ID: PRD_000454
• Descriptor: PROTEIN (PROTEASE), (2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide (3 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22274.19

Authors

Munshi, S. (deposition date: 1999-12-28, release date: 2000-12-28, Last modification date: 2023-12-27)

Primary citation

Munshi, S.,Chen, Z.,Yan, Y.,Li, Y.,Olsen, D.B.,Schock, H.B.,Galvin, B.B.,Dorsey, B.,Kuo, L.C.
An alternate binding site for the P1-P3 group of a class of potent HIV-1 protease inhibitors as a result of concerted structural change in the 80s loop of the protease.
Acta Crystallogr.,Sect.D, 56:381-388, 2000

PubMed Abstract: Structures of the complexes of HIV protease inhibitor L--756,423 with the HIV-1 wild-type protease and of the inhibitors Indinavir, L-739,622 and Saquinavir with the mutant protease (9X) containing nine point mutations (Leu10Val, Lys20Met, Leu24Ile, Ser37Asp, Met46Ile, Ile54Val, Leu63Pro, Ala71Val, Val82Thr) have been determined. Comparative analysis of these structures reveals an alternate binding pocket for the P1-P3 group of Indinavir and L--756, 423. The alternate binding pocket is a result of concerted structural change in the 80s loop (residues 79-82) of the protease. The 80s loop is pulled away from the active site in order to accommodate the P1-P3 group, which is sandwiched between the flap and the 80s loop. This structural change is observed for the complexes of the wild type as well as the 9X mutant protease. The study reveals that the 80s loop is an intrinsically flexible loop in the wild-type HIV-1 protease and that mutations in this loop are not necessary to result in conformational changes. Conformation of this loop in the complex depends primarily upon the nature of the bound inhibitor and may be influenced by mutations in the protease. The results underscore the need to understand the intrinsic structural plasticity of the protease for the design of effective inhibitors against the wild-type and drug-resistant enzyme forms. In addition, the alternate binding pocket for the P1-P3 group of Indinavir and L--756,423 may be exploited for the design of potent inhibitors.

PubMed: 10739910
DOI: 10.1107/S0907444900000469

Experimental method

X-RAY DIFFRACTION (2.5 Å)