6DUH

Crystal structure of HIV-1 reverse transcriptase Y181I mutant in complex with non-nucleoside inhibitor 25a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors.

Yang, Y.Kang, D.Nguyen, L.A.Smithline, Z.B.Pannecouque, C.Zhan, P.Liu, X.Steitz, T.A.

(2018) Elife 7

  • DOI: https://doi.org/10.7554/eLife.36340
  • Primary Citation of Related Structures:  
    6C0J, 6C0K, 6C0L, 6C0N, 6C0O, 6C0P, 6C0R, 6CGF, 6DUF, 6DUG, 6DUH

  • PubMed Abstract: 

    Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2- d ]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 Å resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.


  • Organizational Affiliation

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
p66 RT557Human immunodeficiency virus type 1 BH10Mutation(s): 4 
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)
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 type 1 BH10Mutation(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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
K5C (Subject of Investigation/LOI)
Query on K5C

Download Ideal Coordinates CCD File 
C [auth A]4-({4-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylphenoxy}thieno[3,2-d]pyrimidin-2-yl)amino]piperidin-1-yl}methyl)benzene-1-sulfonamide
C29 H30 N6 O3 S2
GVCHBMCBPBRORW-ONEGZZNKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
AA [auth B]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
AA [auth B],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
Y [auth B],
Z [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
DMS
Query on DMS

Download Ideal Coordinates CCD File 
X [auth B]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
BA [auth B]
CA [auth B]
DA [auth B]
EA [auth B]
FA [auth B]
BA [auth B],
CA [auth B],
DA [auth B],
EA [auth B],
FA [auth B],
GA [auth B],
HA [auth B],
IA [auth B],
J [auth A],
JA [auth B],
K [auth A],
KA [auth B],
L [auth A],
LA [auth B],
M [auth A],
MA [auth B],
N [auth A],
NA [auth B],
O [auth A],
OA [auth B],
P [auth A],
Q [auth A],
R [auth A],
S [auth A],
T [auth A],
U [auth A],
V [auth A],
W [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
K5C BindingDB:  6DUH IC50: min: 99, max: 350 (nM) from 9 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 162.895α = 90
b = 73.229β = 100.3
c = 109.383γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Howard Hughes Medical Institute (HHMI)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-01
    Type: Initial release
  • Version 1.1: 2019-11-20
    Changes: Author supporting evidence
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description