1LZQ

Crystal structure of the complex of mutant HIV-1 protease (A71V, V82T, I84V) with an ethylenamine peptidomimetic inhibitor BOC-PHE-PSI[CH2CH2NH]-PHE-GLU-PHE-NH2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.208 

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This is version 1.5 of the entry. See complete history


Literature

An Ethylenamine Inhibitor Binds Tightly to Both Wild Type and Mutant HIV-1 Proteases. Structure and Energy Study

Skalova, T.Hasek, J.Dohnalek, J.Petrokova, H.Buchtelova, E.Duskova, J.Soucek, M.Majer, P.Uhlikova, T.Konvalinka, J.

(2003) J Med Chem 46: 1636-1644

  • DOI: https://doi.org/10.1021/jm021079g
  • Primary Citation of Related Structures:  
    1LZQ

  • PubMed Abstract: 

    An X-ray structure (resolution 2.2 A) of mutant HIV-1 protease (A71V, V82T, I84V) complexed with a newly developed peptidomimetic inhibitor with an ethylenamine isostere Boc-Phe-Psi[CH(2)CH(2)NH]-Phe-Glu-Phe-NH(2), denoted as OE, is described and compared with the complex of wild-type HIV-1 protease with the same inhibitor (resolution 2.5 A). OE shows tight binding to the wild type (K(i) = 1.5 nM) as well as mutant (K(i) = 4.1 nM) protease. The hydrogen bonds formed, in the case of hydroxyethylamine inhibitors, by a hydroxyl group are, in the case of OE inhibitors, replaced by a bifurcated hydrogen bond from the isosteric NH group to both catalytic aspartates Asp 25 and Asp 125. The binding modes of OE inhibitor to the wild type and mutant protease are similar. However, in the mutant protease, weaker van der Waals interactions of the mutated residues Val 84 and Val 184 with OE were found. This lack of interaction energy is compensated by a new aromatic hydrogen bond between the phenyl ring of the inhibitor in position P1 and the mutated residue Thr 182. Energy analysis based on molecular mechanics has been performed to distinguish between the static and dynamic backgrounds of disorder observed at the mutation sites Thr 82, Val 84, Thr 182, and Val 184.


  • Organizational Affiliation

    Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovského nám. 2, 162 06 Praha 6, Czech Republic. skalova@imc.cas.cz


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEASE RETROPEPSIN
A, B
99Human immunodeficiency virus 1Mutation(s): 3 
EC: 3.4.23.16
UniProt
Find proteins for P03367 (Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI))
Explore P03367 
Go to UniProtKB:  P03367
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03367
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0ZQ
Query on 0ZQ

Download Ideal Coordinates CCD File 
C [auth A]N-{(3S)-3-[(tert-butoxycarbonyl)amino]-4-phenylbutyl}-L-phenylalanyl-L-alpha-glutamyl-L-phenylalaninamide
C38 H49 N5 O7
CBWQRQVEXJTNOT-ZLESDFJESA-N
BME
Query on BME

Download Ideal Coordinates CCD File 
D [auth A]BETA-MERCAPTOETHANOL
C2 H6 O S
DGVVWUTYPXICAM-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0ZQ BindingDB:  1LZQ Ki: min: 1.5, max: 4.1 (nM) from 4 assay(s)
Binding MOAD:  1LZQ Ki: 4.1 (nM) from 1 assay(s)
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.68α = 90
b = 62.68β = 90
c = 83.309γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-04-29
    Type: Initial release
  • Version 1.1: 2007-10-16
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Source and taxonomy, Structure summary, Version format compliance
  • Version 1.3: 2012-12-12
    Changes: Other
  • Version 1.4: 2021-10-27
    Changes: Database references, Derived calculations
  • Version 1.5: 2024-02-14
    Changes: Data collection