3EJ8

Structure of double mutant of human iNOS oxygenase domain with bound immidazole


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.232 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.

Garcin, E.D.Arvai, A.S.Rosenfeld, R.J.Kroeger, M.D.Crane, B.R.Andersson, G.Andrews, G.Hamley, P.J.Mallinder, P.R.Nicholls, D.J.St-Gallay, S.A.Tinker, A.C.Gensmantel, N.P.Mete, A.Cheshire, D.R.Connolly, S.Stuehr, D.J.Aberg, A.Wallace, A.V.Tainer, J.A.Getzoff, E.D.

(2008) Nat Chem Biol 4: 700-707

  • DOI: https://doi.org/10.1038/nchembio.115
  • Primary Citation of Related Structures:  
    3E65, 3E67, 3E68, 3E6L, 3E6N, 3E6O, 3E6T, 3E7G, 3E7I, 3E7M, 3E7S, 3E7T, 3EAH, 3EAI, 3EBD, 3EBF, 3EJ8

  • PubMed Abstract: 

    Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents toward remote specificity pockets, which become accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active site conservation.


  • Organizational Affiliation

    The Scripps Research Institute, Department of Molecular Biology and Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, MB4, La Jolla, California 92037, USA. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nitric oxide synthase, inducible
A, B, C, D
424Homo sapiensMutation(s): 2 
Gene Names: Nos2ANOS2
EC: 1.14.13.39
UniProt & NIH Common Fund Data Resources
Find proteins for P35228 (Homo sapiens)
Explore P35228 
Go to UniProtKB:  P35228
PHAROS:  P35228
GTEx:  ENSG00000007171 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35228
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEC
Query on HEC

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B],
L [auth C],
P [auth D]
HEME C
C34 H34 Fe N4 O4
HXQIYSLZKNYNMH-LJNAALQVSA-N
H4B
Query on H4B

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B],
M [auth C],
Q [auth D]
5,6,7,8-TETRAHYDROBIOPTERIN
C9 H15 N5 O3
FNKQXYHWGSIFBK-RPDRRWSUSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
H [auth A],
K [auth B],
O [auth C],
R [auth D]
IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
ZN
Query on ZN

Download Ideal Coordinates CCD File 
G [auth A],
N [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.232 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 89.883α = 90
b = 150.71β = 90
c = 191.047γ = 90
Software Package:
Software NamePurpose
CNSrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2008-10-07
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.3: 2024-02-21
    Changes: Data collection