1K6V

LACK OF SYNERGY FOR INHIBITORS TARGETING A MULTI-DRUG RESISTANT HIV-1 PROTEASE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease.

King, N.M.Melnick, L.Prabu-Jeyabalan, M.Nalivaika, E.A.Yang, S.S.Gao, Y.Nie, X.Zepp, C.Heefner, D.L.Schiffer, C.A.

(2002) Protein Sci 11: 418-429

  • DOI: https://doi.org/10.1110/ps.25502
  • Primary Citation of Related Structures:  
    1K6C, 1K6P, 1K6T, 1K6V

  • PubMed Abstract: 

    The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements seen in the second tightest inhibitor complex. This occurs as adaptations in the S1 pocket of one monomer propagate through the dimer and affect the conformation of the S1 loop near P81 of the other monomer. Therefore, structural rearrangements that occur within the protease when it binds to an inhibitor with a single modification must be accounted for in the design of inhibitors with multiple modifications. This consideration is necessary to develop inhibitors that bind sufficiently tightly to drug-resistant variants of HIV-1 protease to potentially become the next generation of therapeutic agents.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
POL polyprotein
A, B
99Human immunodeficiency virus 1Mutation(s): 4 
Gene Names: POL
EC: 3.4.23.16
UniProt
Find proteins for P35963 (Human immunodeficiency virus type 1 group M subtype B (isolate YU-2))
Explore P35963 
Go to UniProtKB:  P35963
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35963
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
XN2
Query on XN2

Download Ideal Coordinates CCD File 
G [auth B]N-[2-HYDROXY-1-INDANYL]-5-[(2-TERTIARYBUTYLAMINOCARBONYL)-4(BENZO[1,3]DIOXOL-5-YLMETHYL)-PIPERAZINO]-4-HYDROXY-2-(1-PHE NYLETHYL)-PENTANAMIDE
C39 H50 N4 O6
MJIRDPUZGGHJMX-OIVSQUILSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth B],
F [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
XN2 Binding MOAD:  1K6V Kd: 120 (nM) from 1 assay(s)
PDBBind:  1K6V Kd: 120 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.177 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.445α = 90
b = 59.404β = 90
c = 61.743γ = 90
Software Package:
Software NamePurpose
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2002-02-06
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2023-08-16
    Changes: Data collection, Refinement description