3TKW

Crystal structure of HIV protease model precursor/Darunavir complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.167 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Terminal interface conformations modulate dimer stability prior to amino terminal autoprocessing of HIV-1 protease.

Agniswamy, J.Sayer, J.M.Weber, I.T.Louis, J.M.

(2012) Biochemistry 51: 1041-1050

  • DOI: https://doi.org/10.1021/bi201809s
  • Primary Citation of Related Structures:  
    3TKG, 3TKW, 3TL9

  • PubMed Abstract: 

    The HIV-1 protease (PR) mediates its own release (autoprocessing) from the polyprotein precursor, Gag-Pol, flanked by the transframe region (TFR) and reverse transcriptase at its N- and C-termini, respectively. Autoprocessing at the N-terminus of PR mediates stable dimer formation essential for catalytic activity, leading to the formation of infectious virus. An antiparallel β-sheet interface formed by the four N- and C-terminal residues of each subunit is important for dimer stability. Here, we present the first high-resolution crystal structures of model protease precursor-clinical inhibitor (PI darunavir or saquinavir) complexes, revealing varying conformations of the N-terminal flanking (S(-4)FNF(-1)) and interface residues (P(1)QIT(4)). A 180° rotation of the T(4)-L(5) peptide bond is accompanied by a new Q(2)-L(5) hydrogen bond and complete disengagement of PQIT from the β-sheet dimer interface, which may be a feature for intramolecular autoprocessing. This result is consistent with drastically lower thermal stability by 14-20 °C of PI complexes of precursors and the mature PR lacking its PQIT residues (by 18.3 °C). Similar to the TFR-PR precursor, this deletion also results in a darunavir dissociation constant (2 × 10(4))-fold higher and a markedly increased dimer dissociation constant relative to the mature PR. The terminal β-sheet perturbations of the dimeric structure likely account for the drastically poorer inhibition of autoprocessing of TFR-PR relative to the mature PR, even though significant differences in active site-PI interactions in these structures were not observed. The novel conformations of the dimer interface may be exploited to target selectively the protease precursor prior to its N-terminal cleavage.


  • Organizational Affiliation

    Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, Georgia 30303, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protease
A, B
103Human immunodeficiency virus type 1 (BRU ISOLATE)Mutation(s): 0 
Gene Names: gag-pol
EC: 3.4.23.16
UniProt
Find proteins for P03366 (Human immunodeficiency virus type 1 group M subtype B (isolate BH10))
Explore P03366 
Go to UniProtKB:  P03366
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03366
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
017
Query on 017

Download Ideal Coordinates CCD File 
E [auth B](3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE
C27 H37 N3 O7 S
CJBJHOAVZSMMDJ-HEXNFIEUSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth B],
G [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B],
I [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
D [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
017 BindingDB:  3TKW Ki: min: 2.00e-4, max: 2 (nM) from 17 assay(s)
Kd: 0.02 (nM) from 1 assay(s)
IC50: min: 0.06, max: 370 (nM) from 10 assay(s)
EC50: min: 0.15, max: 112 (nM) from 5 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.167 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.317α = 90
b = 86.223β = 90
c = 45.951γ = 90
Software Package:
Software NamePurpose
SERGUIdata collection
PHASERphasing
SHELXL-97refinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-04-25
    Type: Initial release
  • Version 1.1: 2017-11-08
    Changes: Refinement description
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary