4EJK

HIV Protease (PR) dimer in closed form with pepstatin in active site and fragment 1F1-N in the outside/top of flap


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Small molecule regulation of protein conformation by binding in the Flap of HIV protease.

Tiefenbrunn, T.Forli, S.Baksh, M.M.Chang, M.W.Happer, M.Lin, Y.C.Perryman, A.L.Rhee, J.K.Torbett, B.E.Olson, A.J.Elder, J.H.Finn, M.G.Stout, C.D.

(2013) ACS Chem Biol 8: 1223-1231

  • DOI: https://doi.org/10.1021/cb300611p
  • Primary Citation of Related Structures:  
    4EJ8, 4EJD, 4EJK, 4EJL

  • PubMed Abstract: 

    The fragment indole-6-carboxylic acid (1F1), previously identified as a flap site binder in a fragment-based screen against HIV protease (PR), has been cocrystallized with pepstatin-inhibited PR and with apo-PR. Another fragment, 3-indolepropionic acid (1F1-N), predicted by AutoDock calculations and confirmed in a novel inhibition of nucleation crystallization assay, exploits the same interactions in the flap site in two crystal structures. Both 1F1 and 1F1-N bind to the closed form of apo-PR and to pepstatin:PR. In solution, 1F1 and 1F1-N raise the Tm of apo-PR by 3.5-5 °C as assayed by differential scanning fluorimetry (DSF) and show equivalent low-micromolar binding constants to both apo-PR and pepstatin:PR, assayed by backscattering interferometry (BSI). The observed signal intensities in BSI are greater for each fragment upon binding to apo-PR than to pepstatin-bound PR, consistent with greater conformational change in the former binding event. Together, these data indicate that fragment binding in the flap site favors a closed conformation of HIV PR.


  • Organizational Affiliation

    Deparatment of Integrative Structural and Computational Biology, ‡Department of Chemistry, §Department of Molecular and Experimental Medicine, ∥Department of Immunology and Microbial Science, The Scripps Research Institute , 10550 N. Torrey Pines Rd., La Jolla, California 92037, United States.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protease
A, B
99Human immunodeficiency virus 1Mutation(s): 0 
Gene Names: pol
EC: 3.4.23.16
UniProt
Find proteins for P12499 (Human immunodeficiency virus type 1 group M subtype D (isolate Z2/CDC-Z34))
Explore P12499 
Go to UniProtKB:  P12499
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12499
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
pepstatinC [auth N]6N/AMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
IOP
Query on IOP

Download Ideal Coordinates CCD File 
D [auth A]INDOLYLPROPIONIC ACID
C11 H11 N O2
GOLXRNDWAUTYKT-UHFFFAOYSA-N
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 28.652α = 90
b = 65.796β = 90
c = 92.052γ = 90
Software Package:
Software NamePurpose
SAINTdata scaling
SCALAdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
PROTEUM PLUSdata collection
SAINTdata reduction

Structure Validation

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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: 2014-02-19
    Changes: Database references
  • Version 1.2: 2018-03-07
    Changes: Advisory, Data collection