6DH7

Crystal structure of HIV-1 Protease NL4-3 I50V Mutant in complex with UMass1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease.

Lockbaum, G.J.Leidner, F.Rusere, L.N.Henes, M.Kosovrasti, K.Nachum, G.S.Nalivaika, E.A.Ali, A.Yilmaz, N.K.Schiffer, C.A.

(2019) ACS Infect Dis 5: 316-325

  • DOI: https://doi.org/10.1021/acsinfecdis.8b00336
  • Primary Citation of Related Structures:  
    6DGX, 6DGY, 6DGZ, 6DH0, 6DH1, 6DH2, 6DH3, 6DH4, 6DH5, 6DH6, 6DH7, 6DH8

  • PubMed Abstract: 

    HIV-1 protease is one of the prime targets of agents used in antiretroviral therapy against HIV. However, under selective pressure of protease inhibitors, primary mutations at the active site weaken inhibitor binding to confer resistance. Darunavir (DRV) is the most potent HIV-1 protease inhibitor in clinic; resistance is limited, as DRV fits well within the substrate envelope. Nevertheless, resistance is observed due to hydrophobic changes at residues including I50, V82, and I84 that line the S1/S1' pocket within the active site. Through enzyme inhibition assays and a series of 12 crystal structures, we interrogated susceptibility of DRV and two potent analogues to primary S1' mutations. The analogues had modifications at the hydrophobic P1' moiety compared to DRV to better occupy the unexploited space in the S1' pocket where the primary mutations were located. Considerable losses of potency were observed against protease variants with I84V and I50V mutations for all three inhibitors. The crystal structures revealed an unexpected conformational change in the flap region of I50V protease bound to the analogue with the largest P1' moiety, indicating interdependency between the S1' subsite and the flap region. Collective analysis of protease-inhibitor interactions in the crystal structures using principle component analysis was able to distinguish inhibitor identity and relative potency solely based on van der Waals contacts. Our results reveal the complexity of the interplay between inhibitor P1' moiety and S1' mutations and validate principle component analyses as a useful tool for distinguishing resistance and inhibitor potency.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Pharmacology , University of Massachusetts Medical School , 364 Plantation Street , Worcester , Massachusetts 01605 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ProteaseA [auth B],
B [auth A]
99Human immunodeficiency virus 1Mutation(s): 2 
Gene Names: pol
UniProt
Find proteins for Q7ZCR0 (Human immunodeficiency virus 1)
Explore Q7ZCR0 
Go to UniProtKB:  Q7ZCR0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ7ZCR0
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
K13 (Subject of Investigation/LOI)
Query on K13

Download Ideal Coordinates CCD File 
E [auth A](3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(1S,2R)-3-{[(4-aminophenyl)sulfonyl][(2S)-2-methylbutyl]amino}-1-benzyl-2-hydroxypropyl]carbamate
C28 H39 N3 O7 S
NKLRQHQHYBFPSD-DRMLODCJSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
K13 BindingDB:  6DH7 Ki: min: 6.00e-3, max: 0.01 (nM) from 2 assay(s)
Binding MOAD:  6DH7 Ki: 0.13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.121α = 90
b = 57.818β = 90
c = 62.16γ = 90
Software Package:
Software NamePurpose
HKL-3000data scaling
PHASERphasing
PHENIXrefinement
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesNIH P01 GM109767

Revision History  (Full details and data files)

  • Version 1.0: 2018-12-26
    Type: Initial release
  • Version 1.1: 2019-02-20
    Changes: Data collection, Database references
  • Version 1.2: 2019-12-18
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Refinement description