1IKV

K103N Mutant HIV-1 Reverse Transcriptase in Complex with Efivarenz


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.294 
  • R-Value Work: 0.228 

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Ligand Structure Quality Assessment 


This is version 1.7 of the entry. See complete history


Literature

Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant.

Lindberg, J.Sigurdsson, S.Lowgren, S.Andersson, H.O.Sahlberg, C.Noreen, R.Fridborg, K.Zhang, H.Unge, T.

(2002) Eur J Biochem 269: 1670-1677

  • DOI: https://doi.org/10.1046/j.1432-1327.2002.02811.x
  • Primary Citation of Related Structures:  
    1IKV, 1IKW, 1IKX, 1IKY

  • PubMed Abstract: 

    The K103N substitution is a frequently observed HIV-1 RT mutation in patients who do not respond to combination-therapy. The drugs Efavirenz, MSC194 and PNU142721 belong to the recent generation of NNRTIs characterized by an improved resistance profile to the most common single point mutations within HIV-1 RT, including the K103N mutation. In the present study we present structural observations from Efavirenz in complex with wild-type protein and the K103N mutant and PNU142721 and MSC194 in complex with the K103N mutant. The structures unanimously indicate that the K103N substitution induces only minor positional adjustments of the three inhibitors and the residues lining the binding pocket. Thus, compared to the corresponding wild-type structures, these inhibitors bind to the mutant in a conservative mode rather than through major rearrangements. The structures implicate that the reduced inhibitory efficacy should be attributed to the changes in the chemical environment in the vicinity of the substituted N103 residue. This is supported by changes in hydrophobic and electrostatic interactions to the inhibitors between wild-type and K103N mutant complexes. These potent inhibitors accommodate to the K103N mutation by forming new interactions to the N103 side chain. Our results are consistent with the proposal by Hsiou et al. [Hsiou, Y., Ding, J., Das, K., Clark, A.D. Jr, Boyer, P.L., Lewi, P., Janssen, P.A., Kleim, J.P., Rosner, M., Hughes, S.H. & Arnold, E. (2001) J. Mol. Biol. 309, 437-445] that inhibitors with good activity against the K103N mutant would be expected to have favorable interactions with the mutant asparagines side chain, thereby compensating for resistance caused by stabilization of the mutant enzyme due to a hydrogen-bond network involving the N103 and Y188 side chains.


  • Organizational Affiliation

    Department of Cell and Molecular Biology, Uppsala Biomedical Center, Uppsala University, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
POL POLYPROTEIN560Human immunodeficiency virus 1Mutation(s): 2 
Gene Names: BH10
EC: 2.7.7.49
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
POL POLYPROTEIN427Human immunodeficiency virus 1Mutation(s): 1 
Gene Names: BH10
EC: 2.7.7.49
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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EFZ
Query on EFZ

Download Ideal Coordinates CCD File 
C [auth A](-)-6-CHLORO-4-CYCLOPROPYLETHYNYL-4-TRIFLUOROMETHYL-1,4-DIHYDRO-2H-3,1-BENZOXAZIN-2-ONE
C14 H9 Cl F3 N O2
XPOQHMRABVBWPR-ZDUSSCGKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
EFZ BindingDB:  1IKV Ki: min: 3, max: 380 (nM) from 11 assay(s)
IC50: min: 0.09, max: 800 (nM) from 28 assay(s)
EC50: min: 1, max: 300 (nM) from 5 assay(s)
PDBBind:  1IKV IC50: 520 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.294 
  • R-Value Work: 0.228 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 119.633α = 90
b = 157.168β = 90
c = 156.149γ = 90
Software Package:
Software NamePurpose
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-06-06
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2011-08-31
    Changes: Atomic model
  • Version 1.4: 2012-07-18
    Changes: Non-polymer description
  • Version 1.5: 2018-03-07
    Changes: Advisory, Data collection
  • Version 1.6: 2021-10-27
    Changes: Advisory, Database references, Derived calculations
  • Version 1.7: 2024-02-07
    Changes: Data collection