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PDBsum entry 4k5e

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase/oxidoreductase inhibitor PDB id
4k5e
Jmol
Contents
Protein chains
407 a.a.
Ligands
HEM ×2
H4B ×2
1Q7 ×2
ACT ×2
Metals
_ZN
Waters ×462
PDB id:
4k5e
Name: Oxidoreductase/oxidoreductase inhibitor
Title: Structure of neuronal nitric oxide synthase heme domain in c with (r)-1,2-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-pr amine
Structure: Nitric oxide synthase, brain. Chain: a, b. Fragment: heme domain (unp residues 297-718). Synonym: bnos, constitutive nos, nc-nos, nos type i, neuron nos, nnos, peptidyl-cysteine s-nitrosylase nos1. Engineered: yes
Source: Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: nos1, bnos. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
1.89Å     R-factor:   0.182     R-free:   0.212
Authors: H.Li,T.L.Poulos
Key ref: Q.Jing et al. (2013). Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors. Bioorg Med Chem Lett, 23, 5674-5679. PubMed id: 23993333 DOI: 10.1016/j.bmcl.2013.08.034
Date:
14-Apr-13     Release date:   18-Sep-13    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P29476  (NOS1_RAT) -  Nitric oxide synthase, brain
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1429 a.a.
407 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.1.14.13.39  - Nitric-oxide synthase (Nadph dependent).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 2 L-arginine + 3 NADPH + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
2 × L-arginine
+ 3 × NADPH
+ 4 × O(2)
= 2 × L-citrulline
+ 2 × nitric oxide
+ 3 × NADP(+)
+ 4 × H(2)O
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   2 terms 
  Biochemical function     nitric-oxide synthase activity     1 term  

 

 
    reference    
 
 
DOI no: 10.1016/j.bmcl.2013.08.034 Bioorg Med Chem Lett 23:5674-5679 (2013)
PubMed id: 23993333  
 
 
Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.
Q.Jing, H.Li, G.Chreifi, L.J.Roman, P.Martásek, T.L.Poulos, R.B.Silverman.
 
  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.