4KCR

Structure of bovine endothelial nitric oxide synthase heme domain in complex with N-(3-(((3-fluorophenethyl)amino)methyl)phenyl)thiophene-2-carboximidamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Potent and Selective Double-Headed Thiophene-2-carboximidamide Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma.

Huang, H.Li, H.Yang, S.Chreifi, G.Martasek, P.Roman, L.J.Meyskens, F.L.Poulos, T.L.Silverman, R.B.

(2014) J Med Chem 57: 686-700

  • DOI: https://doi.org/10.1021/jm401252e
  • Primary Citation of Related Structures:  
    4KCH, 4KCI, 4KCJ, 4KCK, 4KCL, 4KCM, 4KCN, 4KCO, 4KCP, 4KCQ, 4KCR, 4KCS

  • PubMed Abstract: 

    Selective inhibitors of neuronal nitric oxide synthase (nNOS) are regarded as valuable and powerful agents with therapeutic potential for the treatment of chronic neurodegenerative pathologies and human melanoma. Here, we describe a novel hybrid strategy that combines the pharmacokinetically promising thiophene-2-carboximidamide fragment and structural features of our previously reported potent and selective aminopyridine inhibitors. Two inhibitors, 13 and 14, show low nanomolar inhibitory potency (Ki = 5 nM for nNOS) and good isoform selectivities (nNOS over eNOS [440- and 540-fold, respectively] and over iNOS [260- and 340-fold, respectively]). The crystal structures of these nNOS-inhibitor complexes reveal a new hot spot that explains the selectivity of 14 and why converting the secondary to tertiary amine leads to enhanced selectivity. More importantly, these compounds are the first highly potent and selective nNOS inhibitory agents that exhibit excellent in vitro efficacy in melanoma cell lines.


  • 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, endothelial
A, B
443Bos taurusMutation(s): 0 
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 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
C [auth A],
J [auth B]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
5H3
Query on 5H3

Download Ideal Coordinates CCD File 
E [auth A],
L [auth B]
N-[3-({[2-(3-fluorophenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide
C20 H20 F N3 S
QJSHZJYEBIUVCD-UHFFFAOYSA-N
H4B
Query on H4B

Download Ideal Coordinates CCD File 
D [auth A],
K [auth B]
5,6,7,8-TETRAHYDROBIOPTERIN
C9 H15 N5 O3
FNKQXYHWGSIFBK-RPDRRWSUSA-N
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 
I [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
M [auth B],
N [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CAS
Query on CAS
A, B
L-PEPTIDE LINKINGC5 H12 As N O2 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
5H3 BindingDB:  4KCR Ki: 900 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 57.641α = 90
b = 106.232β = 90
c = 156.492γ = 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: 2014-02-12
    Type: Initial release
  • Version 1.1: 2014-02-26
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.4: 2024-11-20
    Changes: Structure summary