4K5K

Structure of bovine endothelial nitric oxide synthase heme domain in complex with ((2S, 3S)-1,3-bis((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methoxy)-2-aminobutane


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.

Jing, Q.Li, H.Chreifi, G.Roman, L.J.Martasek, P.Poulos, T.L.Silverman, R.B.

(2013) Bioorg Med Chem Lett 23: 5674-5679

  • DOI: https://doi.org/10.1016/j.bmcl.2013.08.034
  • Primary Citation of Related Structures:  
    4K5D, 4K5E, 4K5F, 4K5G, 4K5H, 4K5I, 4K5J, 4K5K

  • PubMed Abstract: 

    To develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization.


  • Organizational Affiliation

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


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
Q13
Query on Q13

Download Ideal Coordinates CCD File 
E [auth A],
L [auth B]
6,6'-{[(2S,3S)-2-aminobutane-1,3-diyl]bis(oxymethanediyl)}bis(4-methylpyridin-2-amine)
C18 H27 N5 O2
BGQWILAWEWZMTG-BBRMVZONSA-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
Q13 Binding MOAD:  4K5K Ki: 2542 (nM) from 1 assay(s)
BindingDB:  4K5K Ki: min: 2542, max: 3042 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 57.924α = 90
b = 106.472β = 90
c = 156.744γ = 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: 2013-09-18
    Type: Initial release
  • Version 1.1: 2013-10-02
    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