1C6Y

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.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.310 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.180 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

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.

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

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

  • DOI: https://doi.org/10.1107/s0907444900000469
  • Primary Citation of Related Structures:  
    1C6X, 1C6Y, 1C6Z, 1C70

  • 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.


  • Organizational Affiliation

    Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA. sanjeev_munshi@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEIN (PROTEASE)
A, B
99Human immunodeficiency virus 1Mutation(s): 0 
Gene Names: NY5 ISOLATE
EC: 3.4.24
UniProt
Find proteins for O09893 (Human immunodeficiency virus 1)
Explore O09893 
Go to UniProtKB:  O09893
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO09893
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MK1
Query on MK1

Download Ideal Coordinates CCD File 
C [auth B]N-[2(R)-HYDROXY-1(S)-INDANYL]-5-[(2(S)-TERTIARY BUTYLAMINOCARBONYL)-4(3-PYRIDYLMETHYL)PIPERAZINO]-4(S)-HYDROXY-2(R)-PHENYLMETHYLPENTANAMIDE
C36 H47 N5 O4
CBVCZFGXHXORBI-PXQQMZJSSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
MK1 Binding MOAD:  1C6Y Ki: 0.31 (nM) from 1 assay(s)
PDBBind:  1C6Y Ki: 0.31 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.310 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.180 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.44α = 90
b = 88.26β = 90
c = 42.94γ = 90
Software Package:
Software NamePurpose
X-PLORrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2000-12-28 
  • Deposition Author(s): Munshi, S.

Revision History  (Full details and data files)

  • Version 1.0: 2000-12-28
    Type: Initial release
  • Version 1.1: 2008-04-26
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-27
    Changes: Data collection, Database references, Derived calculations