PDBsum entry 4imx

Oxidoreductase/oxidoreductase inhibitor

PDB id

4imx

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Contents

			Protein chains

					405 a.a.

			Ligands

					HEM ×2


					H4B ×2


					1EV ×2


					ACT ×4


					GOL ×2


					CAD ×2

			Metals

					_ZN

			Waters ×249

PDB id:

4imx

Links

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Structure of bovine endothelial nitric oxide synthase heme domain in complex with 3,5-bis(2-(6-amino-4-methylpyridin-2-yl)ethyl) benzonitrile

Structure:

Subunit a. Chain: a, b. Engineered: yes

Source:

Bos taurus. Bovine. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.25Å

R-factor:

0.179

R-free:

0.222

Authors:

H.Li,T.L.Poulos

Key ref:

H.Huang et al. (2013). Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. J Med Chem, 56, 3024-3032. PubMed id: 23451760 DOI: 10.1021/jm4000984

Date:

03-Jan-13

Release date:

24-Apr-13

PROCHECK

	Headers

	References

Protein chains

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 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: 10.1021/jm4000984	J Med Chem 56:3024-3032 (2013)
PubMed id: 23451760

Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.
H.Huang, H.Li, P.Martásek, L.J.Roman, T.L.Poulos, R.B.Silverman.

ABSTRACT

Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of l-arginine to l-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs.