3EAH

Structure of inhibited human eNOS oxygenase domain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.44 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.213 

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Ligand Structure Quality Assessment 


This is version 1.2 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, endothelial
A, B
427Homo sapiensMutation(s): 0 
Gene Names: Nos3
EC: 1.14.13.39
UniProt & NIH Common Fund Data Resources
Find proteins for P29474 (Homo sapiens)
Explore P29474 
Go to UniProtKB:  P29474
PHAROS:  P29474
GTEx:  ENSG00000164867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29474
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEC
Query on HEC

Download Ideal Coordinates CCD File 
C [auth A],
L [auth B]
HEME C
C34 H34 Fe N4 O4
HXQIYSLZKNYNMH-LJNAALQVSA-N
327
Query on 327

Download Ideal Coordinates CCD File 
E [auth A],
M [auth B]
(3S,5E)-3-propyl-3,4-dihydrothieno[2,3-f][1,4]oxazepin-5(2H)-imine
C10 H14 N2 O S
JIIBOYBTIWHZFJ-ZETCQYMHSA-N
MPD
Query on MPD

Download Ideal Coordinates CCD File 
F [auth A],
H [auth A],
I [auth A],
K [auth B]
(4S)-2-METHYL-2,4-PENTANEDIOL
C6 H14 O2
SVTBMSDMJJWYQN-YFKPBYRVSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
D [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.44 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.213 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.09α = 90
b = 90.15β = 90
c = 156.1γ = 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: 2024-02-21
    Changes: Data collection, Database references, Derived calculations