4IMW

Structure of rat neuronal nitric oxide synthase in complex with 3,5-bis(2-(6-amino-4-methylpyridin-2-yl)ethyl)benzonitrile


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.216 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.

Huang, H.Li, H.Martasek, P.Roman, L.J.Poulos, T.L.Silverman, R.B.

(2013) J Med Chem 56: 3024-3032

  • DOI: https://doi.org/10.1021/jm4000984
  • Primary Citation of Related Structures:  
    4IMS, 4IMT, 4IMU, 4IMW, 4IMX

  • PubMed Abstract: 

    Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs.


  • Organizational Affiliation

    Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nitric oxide synthase, brain
A, B
422Rattus norvegicusMutation(s): 0 
Gene Names: Nos1Bnos
EC: 1.14.13.39
UniProt
Find proteins for P29476 (Rattus norvegicus)
Explore P29476 
Go to UniProtKB:  P29476
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29476
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
C [auth A],
I [auth B]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
1EV
Query on 1EV

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B]
3,5-bis[2-(6-amino-4-methylpyridin-2-yl)ethyl]benzonitrile
C23 H25 N5
IXUSJKAERUMZME-UHFFFAOYSA-N
H4B
Query on H4B

Download Ideal Coordinates CCD File 
D [auth A],
G [auth A]
5,6,7,8-TETRAHYDROBIOPTERIN
C9 H15 N5 O3
FNKQXYHWGSIFBK-RPDRRWSUSA-N
ZN
Query on ZN

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

Download Ideal Coordinates CCD File 
E [auth A],
K [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
1EV Binding MOAD:  4IMW Ki: 56 (nM) from 1 assay(s)
BindingDB:  4IMW Ki: 56 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.216 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.685α = 90
b = 111.393β = 90
c = 164.177γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-04-24
    Type: Initial release
  • Version 1.1: 2017-11-15
    Changes: Refinement description
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description