5KR2

Protease PR5-SQV


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Effects of Hinge-region Natural Polymorphisms on Human Immunodeficiency Virus-Type 1 Protease Structure, Dynamics, and Drug Pressure Evolution.

Liu, Z.Huang, X.Hu, L.Pham, L.Poole, K.M.Tang, Y.Mahon, B.P.Tang, W.Li, K.Goldfarb, N.E.Dunn, B.M.McKenna, R.Fanucci, G.E.

(2016) J Biol Chem 291: 22741-22756

  • DOI: https://doi.org/10.1074/jbc.M116.747568
  • Primary Citation of Related Structures:  
    5KQX, 5KQY, 5KQZ, 5KR0, 5KR1, 5KR2

  • PubMed Abstract: 

    Multidrug resistance to current Food and Drug Administration-approved HIV-1 protease (PR) inhibitors drives the need to understand the fundamental mechanisms of how drug pressure-selected mutations, which are oftentimes natural polymorphisms, elicit their effect on enzyme function and resistance. Here, the impacts of the hinge-region natural polymorphism at residue 35, glutamate to aspartate (E35D), alone and in conjunction with residue 57, arginine to lysine (R57K), are characterized with the goal of understanding how altered salt bridge interactions between the hinge and flap regions are associated with changes in structure, motional dynamics, conformational sampling, kinetic parameters, and inhibitor affinity. The combined results reveal that the single E35D substitution leads to diminished salt bridge interactions between residues 35 and 57 and gives rise to the stabilization of open-like conformational states with overall increased backbone dynamics. In HIV-1 PR constructs where sites 35 and 57 are both mutated (e.g. E35D and R57K), x-ray structures reveal an altered network of interactions that replace the salt bridge thus stabilizing the structural integrity between the flap and hinge regions. Despite the altered conformational sampling and dynamics when the salt bridge is disrupted, enzyme kinetic parameters and inhibition constants are similar to those obtained for subtype B PR. Results demonstrate that these hinge-region natural polymorphisms, which may arise as drug pressure secondary mutations, alter protein dynamics and the conformational landscape, which are important thermodynamic parameters to consider for development of inhibitors that target for non-subtype B PR.


  • Organizational Affiliation

    From the Department of Chemistry, University of Florida, Gainesville, Florida 32611 and.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protease PR5-SQV
A, B, C, D
99Human immunodeficiency virus 1Mutation(s): 0 
Gene Names: pol
UniProt
Find proteins for V5YAB1 (Human immunodeficiency virus 1)
Explore V5YAB1 
Go to UniProtKB:  V5YAB1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupV5YAB1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ROC
Query on ROC

Download Ideal Coordinates CCD File 
E [auth A],
F [auth C]
(2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide
C38 H50 N6 O5
QWAXKHKRTORLEM-UGJKXSETSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ROC BindingDB:  5KR2 Ki: min: 0.04, max: 138 (nM) from 29 assay(s)
Kd: min: 0.31, max: 67 (nM) from 6 assay(s)
IC50: min: 0.05, max: 270 (nM) from 18 assay(s)
-TΔS: min: -8.03e+1, max: -2.80e+1 (kJ/mol) from 47 assay(s)
ΔH: min: -3.18e+1, max: 43.47 (kJ/mol) from 47 assay(s)
ΔG: min: -6.23e+1, max: -3.55e+1 (kJ/mol) from 44 assay(s)
Binding MOAD:  5KR2 Ki: 3.3 (nM) from 1 assay(s)
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.89α = 90
b = 62.67β = 98.59
c = 58.4γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM105409
National Institutes of Health/National Center for Research Resources (NIH/NCRR)United StatesS10RR031603
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesR37 AI28571

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-21
    Type: Initial release
  • Version 1.1: 2016-11-16
    Changes: Database references
  • Version 1.2: 2017-09-20
    Changes: Author supporting evidence, Database references, Derived calculations
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references, Derived calculations, Structure summary