PDBsum entry 1c6y

Hydrolase

PDB id: 1c6y

Contents

Protein chains

99 a.a. *

Ligands

MK1

Waters ×84

* Residue conservation analysis

PDB id:

1c6y

Name:

Hydrolase

Title:

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.

Structure:

Protein (protease). Chain: a, b. Engineered: yes. Other_details: ny5 isolate

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: ny5 isolate. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

2.50Å R-factor: 0.180 R-free: 0.310

Authors:

S.Munshi

Key ref:

S.Munshi et al. (2000). 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 D Biol Crystallogr, 56, 381-388. PubMed id: 10739910 DOI: 10.1107/S0907444900000469

Date:

28-Dec-99 Release date: 28-Dec-00

Protein chains

O09893  (O09893_9HIV1) -  Protease (Fragment) from Human immunodeficiency virus 1

Seq: 99 a.a.

Struc: 99 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.24.- - ?????

DOI no: 10.1107/S0907444900000469

Acta Crystallogr D Biol Crystallogr 56:381-388 (2000)

PubMed id: 10739910

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.

S.Munshi, Z.Chen, Y.Yan, Y.Li, D.B.Olsen, H.B.Schock, B.B.Galvin, B.Dorsey, L.C.Kuo.

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.

Selected figure(s)

Figure 1.
Figure 1 Chemical structures of the HIV-1 protease inhibitors used in the present studies. (I) Indinavir; (II) L-756,423; (III) L-739,622; (IV) Saquinavir.

Figure 2.
Figure 2 Superposition of the crystal structures of wild-type HIV-1 protease complexed with (I) (blue) and (II) (green). The 80s loop, comprised of residues 79-83, and the flap residues 47-54 of the two monomers are depicted. The inhibitor structures are represented as ball-and-stick models. (a) The P1-P3 (benzofuran) of (II) is sandwiched between the 80s loop and the flap. Pro81 is pulled away by 2.0 Å in order to accommodate the P1-P3 group. (b) The 2|F[o]| - |F[c]| map contoured at 1.0 represents the electron density for the 80s loop in the complex of wild-type protease with (II). The map was computed using phases from the initial protein model without any inhibitor (blue) which had been optimized by rigid-body refinement. The final refined model of the 80s loop and the inhibitor (II) are depicted in green. (c) The P1-P3 (pyridyl group in blue) of (I) interacts with Arg8 and is exposed to solvent. In contrast, the P1-P3 (benzofuran group in green) of (II) is sandwiched between the 80s loop and the flap and does not interact with Arg8. Instead, Arg8 interacts with the water molecules, represented as colored dots.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2000, 56, 381-388) copyright 2000.

Figures were selected by an automated process.