5HRP

HIV Integrase Catalytic Domain containing F185K + A124T mutations complexed with GSK0002


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase.

Gupta, K.Turkki, V.Sherrill-Mix, S.Hwang, Y.Eilers, G.Taylor, L.McDanal, C.Wang, P.Temelkoff, D.Nolte, R.T.Velthuisen, E.Jeffrey, J.Van Duyne, G.D.Bushman, F.D.

(2016) PLoS Biol 14: e1002584-e1002584

  • DOI: https://doi.org/10.1371/journal.pbio.1002584
  • Primary Citation of Related Structures:  
    5HOT, 5HRN, 5HRP, 5HRR, 5HRS

  • PubMed Abstract: 

    The allosteric inhibitors of integrase (termed ALLINIs) interfere with HIV replication by binding to the viral-encoded integrase (IN) protein. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. To investigate the ALLINI inhibitory mechanism, we crystallized full-length HIV-1 IN bound to the ALLINI GSK1264 and determined the structure of the complex at 4.4 Å resolution. The structure shows GSK1264 buried between the IN C-terminal domain (CTD) and the catalytic core domain. In the crystal lattice, the interacting domains are contributed by two different dimers so that IN forms an open polymer mediated by inhibitor-bridged contacts; the N-terminal domains do not participate and are structurally disordered. Engineered amino acid substitutions at the inhibitor interface blocked ALLINI-induced multimerization. HIV escape mutants with reduced sensitivity to ALLINIs commonly altered amino acids at or near the inhibitor-bound interface, and these substitutions also diminished IN multimerization. We propose that ALLINIs inhibit particle assembly by stimulating inappropriate polymerization of IN via interactions between the catalytic core domain and the CTD and that understanding the interface involved offers new routes to inhibitor optimization.


  • Organizational Affiliation

    Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Integrase164HIV-1 M:B_HXB2RMutation(s): 2 
Gene Names: gag-pol
UniProt
Find proteins for P04585 (Human immunodeficiency virus type 1 group M subtype B (isolate HXB2))
Explore P04585 
Go to UniProtKB:  P04585
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04585
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
65P
Query on 65P

Download Ideal Coordinates CCD File 
K [auth A](2S)-tert-butoxy[1-(3,4-difluorobenzyl)-6-methyl-4-(5-methyl-3,4-dihydro-2H-chromen-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]acetic acid
C31 H32 F2 N2 O4
FCHYUVWFDGOTFV-NDEPHWFRSA-N
CAC
Query on CAC

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
CACODYLATE ION
C2 H6 As O2
OGGXGZAMXPVRFZ-UHFFFAOYSA-M
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
G [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A],
J [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.817α = 90
b = 72.817β = 90
c = 65.867γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
BUSTERrefinement
PDB_EXTRACTdata extraction
Cootmodel building
PHASERphasing
DENZOdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-12-14 
  • Deposition Author(s): Nolte, R.T.

Revision History  (Full details and data files)

  • Version 1.0: 2016-12-14
    Type: Initial release
  • Version 1.1: 2016-12-21
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references