8DXK

HIV-1 reverse transcriptase/rilpivirine with bound fragment 4-bromopyrazole at multiple sites


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Halo Library, a Tool for Rapid Identification of Ligand Binding Sites on Proteins Using Crystallographic Fragment Screening.

Chopra, A.Bauman, J.D.Ruiz, F.X.Arnold, E.

(2023) J Med Chem 66: 6013-6024

  • DOI: https://doi.org/10.1021/acs.jmedchem.2c01681
  • Primary Citation of Related Structures:  
    8DX2, 8DX3, 8DX8, 8DXB, 8DXE, 8DXG, 8DXH, 8DXI, 8DXJ, 8DXK, 8DXL, 8DXM

  • PubMed Abstract: 

    X-ray crystallographic fragment screening (XCFS) uses fragment-sized molecules (∼60 to 300 Da) to access binding sites on proteins that may be inaccessible to larger drug-like molecules (>300 Da). Previous studies have shown that fragments containing halogen atoms bind more often to proteins than non-halogenated fragments. Here, we designed the Halo Library containing 46 halogenated fragments (including the "universal fragment" 4-bromopyrazole), a majority of which have been reported to bind to or inhibit one or more targets. The library was screened against the crystals of HIV-1 reverse transcriptase with the drug rilpivirine, yielding an overall hit rate of 26%. Two new binding sites were discovered, and several hot spots were identified. This small library may thus provide a convenient tool for rapidly assessing the feasibility of a target for XCFS, mapping hot spots and cryptic sites, as well as finding fragment binders that can be useful for developing drug leads.


  • Organizational Affiliation

    Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Reverse transcriptase/ribonuclease H557Human immunodeficiency virus type 1 BH10Mutation(s): 3 
Gene Names: gag-pol
EC: 2.7.7.49 (PDB Primary Data), 2.7.7.7 (PDB Primary Data), 3.1.26.13 (PDB Primary Data), 3.1.13.2 (PDB Primary Data)
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
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
p51 RT428Human immunodeficiency virus 1Mutation(s): 1 
Gene Names: gag-pol
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 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
T27
Query on T27

Download Ideal Coordinates CCD File 
C [auth A]4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile
C22 H18 N6
YIBOMRUWOWDFLG-ONEGZZNKSA-N
BYZ (Subject of Investigation/LOI)
Query on BYZ

Download Ideal Coordinates CCD File 
K [auth A]
L [auth A]
M [auth A]
N [auth A]
O [auth A]
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
W [auth B],
X [auth B],
Y [auth B]
4-bromo-1H-pyrazole
C3 H3 Br N2
WVGCPEDBFHEHEZ-UHFFFAOYSA-N
SO4
Query on SO4

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

Download Ideal Coordinates CCD File 
D [auth A]
P [auth B]
Q [auth B]
R [auth B]
S [auth B]
D [auth A],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
U [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
G [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
T27 BindingDB:  8DXK IC50: min: 0.68, max: 84 (nM) from 15 assay(s)
EC50: min: 0.2, max: 3.6 (nM) from 7 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 162.471α = 90
b = 72.983β = 100.685
c = 109.316γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHENIXphasing

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 Allergy and Infectious Diseases (NIH/NIAID)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2023-05-31
    Type: Initial release
  • Version 1.1: 2023-10-25
    Changes: Data collection, Refinement description