4JLH

HIV-1 Integrase Catalytic Core Domain A128T Mutant Complexed with Allosteric Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

The A128T Resistance Mutation Reveals Aberrant Protein Multimerization as the Primary Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors.

Feng, L.Sharma, A.Slaughter, A.Jena, N.Koh, Y.Shkriabai, N.Larue, R.C.Patel, P.A.Mitsuya, H.Kessl, J.J.Engelman, A.Fuchs, J.R.Kvaratskhelia, M.

(2013) J Biol Chem 288: 15813-15820

  • DOI: https://doi.org/10.1074/jbc.M112.443390
  • Primary Citation of Related Structures:  
    4GVM, 4GW6, 4JLH

  • PubMed Abstract: 

    Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a very promising new class of anti-HIV-1 agents that exhibit a multimodal mechanism of action by allosterically modulating IN multimerization and interfering with IN-lens epithelium-derived growth factor (LEDGF)/p75 binding. Selection of viral strains under ALLINI pressure has revealed an A128T substitution in HIV-1 IN as a primary mechanism of resistance. Here, we elucidated the structural and mechanistic basis for this resistance. The A128T substitution did not affect the hydrogen bonding between ALLINI and IN that mimics the IN-LEDGF/p75 interaction but instead altered the positioning of the inhibitor at the IN dimer interface. Consequently, the A128T substitution had only a minor effect on the ALLINI IC50 values for IN-LEDGF/p75 binding. Instead, ALLINIs markedly altered the multimerization of IN by promoting aberrant higher order WT (but not A128T) IN oligomers. Accordingly, WT IN catalytic activities and HIV-1 replication were potently inhibited by ALLINIs, whereas the A128T substitution in IN resulted in significant resistance to the inhibitors both in vitro and in cell culture assays. The differential multimerization of WT and A128T INs induced by ALLINIs correlated with the differences in infectivity of HIV-1 progeny virions. We conclude that ALLINIs primarily target IN multimerization rather than IN-LEDGF/p75 binding. Our findings provide the structural foundations for developing improved ALLINIs with increased potency and decreased potential to select for drug resistance.


  • Organizational Affiliation

    Center for Retrovirus Research, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 Integrase catalytic core domain163Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)Mutation(s): 2 
UniProt
Find proteins for P12497 (Human immunodeficiency virus type 1 group M subtype B (isolate NY5))
Explore P12497 
Go to UniProtKB:  P12497
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12497
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0L9
Query on 0L9

Download Ideal Coordinates CCD File 
B [auth A](2S)-[6-bromo-4-(4-chlorophenyl)-2-methylquinolin-3-yl](methoxy)ethanoic acid
C19 H15 Br Cl N O3
BNDPDYQQAJUJPY-SFHVURJKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CAF
Query on CAF
A
L-PEPTIDE LINKINGC5 H12 As N O3 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
0L9 BindingDB:  4JLH Kd: 4700 (nM) from 1 assay(s)
IC50: min: 28, max: 2.62e+5 (nM) from 7 assay(s)
PDBBind:  4JLH IC50: 4000 (nM) from 1 assay(s)
Binding MOAD:  4JLH IC50: 1.56e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.21α = 90
b = 72.21β = 90
c = 65.9γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-01
    Type: Initial release
  • Version 1.1: 2013-05-08
    Changes: Database references
  • Version 1.2: 2013-06-19
    Changes: Database references
  • Version 1.3: 2017-11-15
    Changes: Refinement description