3LPT

HIV integrase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.233 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication.

Christ, F.Voet, A.Marchand, A.Nicolet, S.Desimmie, B.A.Marchand, D.Bardiot, D.Van der Veken, N.J.Van Remoortel, B.Strelkov, S.V.De Maeyer, M.Chaltin, P.Debyser, Z.

(2010) Nat Chem Biol 6: 442-448

  • DOI: https://doi.org/10.1038/nchembio.370
  • Primary Citation of Related Structures:  
    3LPT, 3LPU

  • PubMed Abstract: 

    Lens epithelium-derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase that promotes viral integration by tethering the preintegration complex to the chromatin. By virtue of its crucial role in the early steps of HIV replication, the interaction between LEDGF/p75 and integrase represents an attractive target for antiviral therapy. We have rationally designed a series of 2-(quinolin-3-yl)acetic acid derivatives (LEDGINs) that act as potent inhibitors of the LEDGF/p75-integrase interaction and HIV-1 replication at submicromolar concentration by blocking the integration step. A 1.84-A resolution crystal structure corroborates the binding of the inhibitor in the LEDGF/p75-binding pocket of integrase. Together with the lack of cross-resistance with two clinical integrase inhibitors, these findings define the 2-(quinolin-3-yl)acetic acid derivatives as the first genuine allosteric HIV-1 integrase inhibitors. Our work demonstrates the feasibility of rational design of small molecules inhibiting the protein-protein interaction between a viral protein and a cellular host factor.


  • Organizational Affiliation

    Laboratory for Molecular Virology and Gene Therapy, Division of Molecular Medicine, Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Integrase166Human immunodeficiency virus 1Mutation(s): 1 
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 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
723
Query on 723

Download Ideal Coordinates CCD File 
B [auth A](6-chloro-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)acetic acid
C17 H12 Cl N O3
SHDUUQWYFNJIAG-UHFFFAOYSA-N
P03
Query on P03

Download Ideal Coordinates CCD File 
F [auth A]2-[3-[3-(2-hydroxyethoxy)propoxy]propoxy]ethanol
C10 H22 O5
GNAZJSIZGCDIQL-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A],
G [auth A]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A],
J [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
CA
Query on CA

Download Ideal Coordinates CCD File 
K [auth A]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
L [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
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
723 BindingDB:  3LPT IC50: 1.17e+4 (nM) from 1 assay(s)
PDBBind:  3LPT IC50: 1.22e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.233 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72α = 90
b = 72β = 90
c = 65.49γ = 120
Software Package:
Software NamePurpose
MAR345dtbdata collection
REFMACrefinement
MOSFLMdata reduction
SCALAdata 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: 2010-05-12
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2015-12-09
    Changes: Database references
  • Version 1.3: 2017-11-01
    Changes: Refinement description
  • Version 1.4: 2021-11-10
    Changes: Database references, Derived calculations
  • Version 1.5: 2024-10-30
    Changes: Data collection, Structure summary