3E68

Structure of murine INOS oxygenase domain with inhibitor AR-C130232


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.247 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 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
433Mus musculusMutation(s): 0 
Gene Names: Nos2Inosl
EC: 1.14.13.39
UniProt & NIH Common Fund Data Resources
Find proteins for P29477 (Mus musculus)
Explore P29477 
Go to UniProtKB:  P29477
IMPC:  MGI:97361
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29477
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
H [auth A],
Q [auth B]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
BOG
Query on BOG

Download Ideal Coordinates CCD File 
C [auth A],
M [auth B]
octyl beta-D-glucopyranoside
C14 H28 O6
HEGSGKPQLMEBJL-RKQHYHRCSA-N
AT6
Query on AT6

Download Ideal Coordinates CCD File 
G [auth A],
P [auth B]
N-[2-(6-AMINO-4-METHYLPYRIDIN-2-YL)ETHYL]-4-CYANOBENZAMIDE
C16 H16 N4 O
QINCZVSBLITNRD-UHFFFAOYSA-N
H4B
Query on H4B

Download Ideal Coordinates CCD File 
I [auth A],
R [auth B]
5,6,7,8-TETRAHYDROBIOPTERIN
C9 H15 N5 O3
FNKQXYHWGSIFBK-RPDRRWSUSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
N [auth B],
O [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
J [auth A]
K [auth A]
L [auth A]
S [auth B]
T [auth B]
J [auth A],
K [auth A],
L [auth A],
S [auth B],
T [auth B],
U [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AT6 BindingDB:  3E68 IC50: 120 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.247 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 213.779α = 90
b = 213.779β = 90
c = 115.75γ = 120
Software Package:
Software NamePurpose
CNSrefinement
PDB_EXTRACTdata extraction
MAR345data collection
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



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: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Data collection, Derived calculations, Structure summary
  • Version 1.4: 2024-02-21
    Changes: Data collection, Database references, Structure summary