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PDBsum entry 1zzt
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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1zzt

 

 

 

 

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Contents
Protein chains
405 a.a. *
Ligands
ACT ×2
HEM ×2
H4B ×2
DP9 ×2
Metals
_ZN
Waters ×372
* Residue conservation analysis
PDB id:
1zzt
Name: Oxidoreductase
Title: Bovine enos n368d/v106m double mutant with l-n(omega)-nitroarginine- (4r)-amino-l-proline amide bound
Structure: Nitric-oxide synthase, endothelial. Chain: a, b. Synonym: ec-nos, nos, type iii, nosiii, endothelial nos, enos, constitutive nos, cnos. Engineered: yes. Mutation: yes
Source: Bos taurus. Cattle. Organism_taxid: 9913. Gene: nos3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.14Å     R-factor:   0.189     R-free:   0.233
Authors: H.Li,M.L.Flinspach,J.Igarashi,J.Jamal,W.Yang,J.A.Gomez-Vidal, E.A.Litzinger,R.B.Silverman,T.L.Poulos
Key ref:
H.Li et al. (2005). Exploring the binding conformations of bulkier dipeptide amide inhibitors in constitutive nitric oxide synthases. Biochemistry, 44, 15222-15229. PubMed id: 16285725 DOI: 10.1021/bi0513610
Date:
14-Jun-05     Release date:   06-Dec-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P29473  (NOS3_BOVIN) -  Nitric oxide synthase 3 from Bos taurus
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1205 a.a.
405 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.1.14.13.39  - nitric-oxide synthase (NADPH).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 2 L-arginine + 3 NADPH + 4 O2 + H+ = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
2 × L-arginine
 +
3 × NADPH
Bound ligand (Het Group name = DP9)
matches with 45.83% similarity 		+ 4 × O2
 + H(+)
 = 2 × L-citrulline
 + 2 × nitric oxide
 + 3 × NADP(+)
 + 4 × H2O
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/bi0513610 Biochemistry 44:15222-15229 (2005)
PubMed id: 16285725  
 
 
Exploring the binding conformations of bulkier dipeptide amide inhibitors in constitutive nitric oxide synthases.
H.Li, M.L.Flinspach, J.Igarashi, J.Jamal, W.Yang, J.A.Gómez-Vidal, E.A.Litzinger, H.Huang, E.P.Erdal, R.B.Silverman, T.L.Poulos.
 
  ABSTRACT  
 
A series of L-nitroarginine-based dipeptide inhibitors are highly selective for neuronal nitric oxide synthase (nNOS) over the endothelial isoform (eNOS). Crystal structures of these dipeptides bound to both isoforms revealed two different conformations, curled in nNOS and extended in eNOS, corresponding to higher and lower binding affinity to the two isoforms, respectively. In previous studies we found that the primary reason for selectivity is that Asp597 in nNOS, which is Asn368 in eNOS, provides greater electrostatic stabilization in the inhibitor complex. While this is the case for smaller dipeptide inhibitors, electrostatic stabilization may no longer be the sole determinant for isoform selectivity with bulkier dipeptide inhibitors. Another residue farther away from the active site, Met336 in nNOS (Val106 in eNOS), is in contact with bulkier dipeptide inhibitors. Double mutants were made to exchange the D597/M336 pair in nNOS with N368/V106 in eNOS. Here we report crystal structures and inhibition constants for bulkier dipeptide inhibitors bound to nNOS and eNOS that illustrate the important role played by residues near the entry to the active site in isoform selective inhibition.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19125620 H.Ji, H.Li, P.Martásek, L.J.Roman, T.L.Poulos, and R.B.Silverman (2009).
Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping.
  J Med Chem, 52, 779-797.  
19235180 H.Ji, S.Tan, J.Igarashi, H.Li, M.Derrick, P.Martásek, L.J.Roman, J.Vásquez-Vivar, T.L.Poulos, and R.B.Silverman (2009).
Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy.
  Ann Neurol, 65, 209-217.  
19154146 R.B.Silverman (2009).
Design of selective neuronal nitric oxide synthase inhibitors for the prevention and treatment of neurodegenerative diseases.
  Acc Chem Res, 42, 439-451.  
18849972 E.D.Garcin, A.S.Arvai, R.J.Rosenfeld, M.D.Kroeger, B.R.Crane, G.Andersson, G.Andrews, P.J.Hamley, P.R.Mallinder, D.J.Nicholls, S.A.St-Gallay, A.C.Tinker, N.P.Gensmantel, A.Mete, D.R.Cheshire, S.Connolly, D.J.Stuehr, A.Aberg, A.V.Wallace, J.A.Tainer, and E.D.Getzoff (2008).
Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.
  Nat Chem Biol, 4, 700-707.
PDB codes: 3e65 3e67 3e68 3e6l 3e6n 3e6o 3e6t 3e7g 3e7i 3e7m 3e7s 3e7t 3eah 3eai 3ebd 3ebf 3ej8
17614291 E.P.Erdal, P.Martásek, L.J.Roman, and R.B.Silverman (2007).
Hydroxyethylene isosteres of selective neuronal nitric oxide synthase inhibitors.
  Bioorg Med Chem, 15, 6096-6108.  
17034131 H.Ji, J.A.Gómez-Vidal, P.Martasek, L.J.Roman, and R.B.Silverman (2006).
Conformationally restricted dipeptide amides as potent and selective neuronal nitric oxide synthase inhibitors.
  J Med Chem, 49, 6254-6263.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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