3DQT

Structure of endothelial NOS heme domain in complex with a inhibitor (+-)-N1-{trans-4'-[(6"-amino-4"-methylpyridin-2"-yl)methyl]pyrrolidin-3'-yl}-N2-(3'-chlorobenzyl)ethane-1,2-diamine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.54 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Crystal structures of constitutive nitric oxide synthases in complex with de novo designed inhibitors.

Igarashi, J.Li, H.Jamal, J.Ji, H.Fang, J.Lawton, G.R.Silverman, R.B.Poulos, T.L.

(2009) J Med Chem 52: 2060-2066

  • DOI: https://doi.org/10.1021/jm900007a
  • Primary Citation of Related Structures:  
    3B3O, 3B3P, 3DQR, 3DQS, 3DQT

  • PubMed Abstract: 

    New nitric oxide synthase (NOS) inhibitors were designed de novo with knowledge gathered from the studies on the nNOS-selective dipeptide inhibitors. Each of the new inhibitors consists of three fragments: an aminopyridine ring, a pyrrolidine, and a tail of various length and polarity. The in vitro inhibitory assays indicate good potency and isoform selectivity for some of the compounds. Crystal structures of these inhibitors bound to either wild type or mutant nNOS and eNOS have confirmed design expectations. The aminopyridine ring mimics the guanidinium group of L-arginine and functions as an anchor to place the compound in the NOS active site where it hydrogen bonds to a conserved Glu. The rigidity of the pyrrolidine ring places the pyrrolidine ring nitrogen between the same conserved Glu and the selective residue nNOS Asp597/eNOS Asn368, which results in similar interactions observed with the alpha-amino group of dipeptide inhibitors bound to nNOS. These structures provide additional information to help in the design of inhibitors with greater potency, physicochemical properties, and isoform selectivity.


  • Organizational Affiliation

    Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, California 92697-3900, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nitric oxide synthase, endothelial
A, B
416Bos taurusMutation(s): 1 
Gene Names: NOS3
EC: 1.14.13.39
UniProt
Find proteins for P29473 (Bos taurus)
Explore P29473 
Go to UniProtKB:  P29473
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29473
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
E [auth A],
L [auth B]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
JI7
Query on JI7

Download Ideal Coordinates CCD File 
G [auth A],
N [auth B]
N-{(3R,4S)-4-[(6-amino-4-methylpyridin-2-yl)methyl]pyrrolidin-3-yl}-N'-(3-chlorobenzyl)ethane-1,2-diamine
C20 H28 Cl N5
VWCMAGONQJHIJZ-LPHOPBHVSA-N
H4B
Query on H4B

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

Download Ideal Coordinates CCD File 
C [auth A],
I [auth B]
CACODYLATE ION
C2 H6 As O2
OGGXGZAMXPVRFZ-UHFFFAOYSA-M
GOL
Query on GOL

Download Ideal Coordinates CCD File 
H [auth A],
O [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

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

Download Ideal Coordinates CCD File 
D [auth A],
J [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
JI7 BindingDB:  3DQT Ki: min: 9.52e+4, max: 9.52e+4 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.54 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.197 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.25α = 90
b = 106.49β = 90
c = 156.42γ = 90
Software Package:
Software NamePurpose
CNSrefinement
ADSCdata collection
HKL-2000data reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-31
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations