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PDBsum entry 3eah
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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
3eah

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
399 a.a. *
Ligands
HEC ×2
327 ×2
MPD ×4
Metals
_ZN
_CL ×2
Waters ×143
* Residue conservation analysis
PDB id:
3eah
Name: Oxidoreductase
Title: Structure of inhibited human enos oxygenase domain
Structure: Nitric oxide synthase, endothelial. Chain: a, b. Synonym: nos type iii, endothelial nos, cnos, enos, nosiii, ec-nos, constitutive nos. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: nos3. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.44Å     R-factor:   0.213     R-free:   0.258
Authors: 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,E.D.Getzoff
Key ref:
E.D.Garcin et al. (2008). Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase. Nat Chem Biol, 4, 700-707. PubMed id: 18849972 DOI: 10.1038/nchembio.115
Date:
25-Aug-08     Release date:   07-Oct-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P29474  (NOS3_HUMAN) -  Nitric oxide synthase 3 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1203 a.a.
399 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).
[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
 + 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: 10.1038/nchembio.115 Nat Chem Biol 4:700-707 (2008)
PubMed id: 18849972  
 
 
Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.
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, E.D.Getzoff.
 
  ABSTRACT  
 
Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents toward remote specificity pockets, which become accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active site conservation.
 
  Selected figure(s)  
 
Figure 3.
(a) Solvent-accessible surfaces for the iNOS (left) and eNOS (right) active sites colored according to Figure 2. The core of compound 9 binds closer and more parallel to the heme in eNOS. In iNOS, side chain rotations of Gln, Arg and Arg388 open the Gln specificity pocket for binding of the bulky inhibitor tail. (b) Stereoview of the superimposition of bovine eNOS–compound 9 (yellow) and human iNOS–compound 9 (blue) X-ray structures, highlighting the cascade of conformational changes of first-shell and second-shell residues upon inhibitor binding to iNOS. 		Figure 5.
Moderately selective compound 16 binds to mouse iNOSox similarly to bulky quinazoline and aminopyridine inhibitors and induces the Gln-open conformation. Residues are colored according to Figure 2. The F[o] – F[c] electron density map contoured at 3 (blue mesh) is shown around the inhibitor (pink).
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2008, 4, 700-707) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21398123 D.R.Cheshire, A.Åberg, G.M.Andersson, G.Andrews, H.G.Beaton, T.N.Birkinshaw, N.Boughton-Smith, S.Connolly, T.R.Cook, A.Cooper, S.L.Cooper, D.Cox, J.Dixon, N.Gensmantel, P.J.Hamley, R.Harrison, P.Hartopp, H.Käck, P.D.Leeson, T.Luker, A.Mete, I.Millichip, D.J.Nicholls, A.D.Pimm, S.A.St-Gallay, and A.V.Wallace (2011).
The discovery of novel, potent and highly selective inhibitors of inducible nitric oxide synthase (iNOS).
  Bioorg Med Chem Lett, 21, 2468-2471.
PDB codes: 2y37 4ux6
21441914 G.J.Williams, R.S.Williams, J.S.Williams, G.Moncalian, A.S.Arvai, O.Limbo, G.Guenther, S.SilDas, M.Hammel, P.Russell, and J.A.Tainer (2011).
ABC ATPase signature helices in Rad50 link nucleotide state to Mre11 interface for DNA repair.
  Nat Struct Mol Biol, 18, 423-431.
PDB codes: 3qkr 3qks 3qkt 3qku
21482467 R.J.Young, W.Alderton, A.D.Angell, P.J.Beswick, D.Brown, C.L.Chambers, M.C.Crowe, J.Dawson, C.C.Hamlett, S.T.Hodgson, S.Kleanthous, R.G.Knowles, L.J.Russell, R.Stocker, and J.M.Woolven (2011).
Heteroalicyclic carboxamidines as inhibitors of inducible nitric oxide synthase; the identification of (2R)-2-pyrrolidinecarboxamidine as a potent and selective haem-co-ordinating inhibitor.
  Bioorg Med Chem Lett, 21, 3037-3040.  
20086004 B.A.Patel, and B.R.Crane (2010).
When it comes to antibiotics, bacteria show some NO-how.
  J Mol Cell Biol, 2, 234-236.  
19951943 C.Giroud, M.Moreau, T.A.Mattioli, V.Balland, J.L.Boucher, Y.Xu-Li, D.J.Stuehr, and J.Santolini (2010).
Role of arginine guanidinium moiety in nitric-oxide synthase mechanism of oxygen activation.
  J Biol Chem, 285, 7233-7245.  
19690675 C.Feng, and G.Tollin (2009).
Regulation of interdomain electron transfer in the NOS output state for NO production.
  Dalton Trans, (), 6692-6700.  
19524664 H.Hong, J.Sun, and W.Cai (2009).
Multimodality imaging of nitric oxide and nitric oxide synthases.
  Free Radic Biol Med, 47, 684-698.  
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.  
19501598 J.J.Perry, R.M.Harris, D.Moiani, A.J.Olson, and J.A.Tainer (2009).
p38alpha MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses.
  J Mol Biol, 391, 1.
PDB code: 3hvc
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.  
19663506 Y.Wang, A.F.Monzingo, S.Hu, T.H.Schaller, J.D.Robertus, and W.Fast (2009).
Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide.
  Biochemistry, 48, 8624-8635.
PDB codes: 3i2e 3i4a
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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