PDBsum entry 4d3v

Oxidoreductase

PDB id: 4d3v

Contents

Protein chain

362 a.a.

Ligands

HEM

RFQ

POL ×3

GOL ×3

Metals

_CL

Waters ×272

PDB id:

4d3v

Name:

Oxidoreductase

Title:

Structure of bacillus subtilis nitric oxide synthase i218v in complex with n-{3-[(1s)-2-(3-{(z)-[amino(thiophen-2-yl) methylidene]amino}phenoxy)-1-hydroxyethyl]phenyl}thiophene-2- carboximidamide

Structure:

Nitric oxide synthase oxygenase. Chain: a. Synonym: nosoxy-like protein. Engineered: yes. Mutation: yes

Source:

Bacillus subtilis subsp. Subtilis str. 168. Organism_taxid: 224308. Atcc: 23857. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.88Å R-factor: 0.174 R-free: 0.209

Authors:

J.K.Holden,T.L.Poulos

Key ref:

J.K.Holden et al. (2015). Structure-based design of bacterial nitric oxide synthase inhibitors. J Med Chem, 58, 994. PubMed id: 25522110 DOI: 10.1021/jm501723p

Date:

23-Oct-14 Release date: 14-Jan-15

Protein chain

O34453  (NOSO_BACSU) -  Nitric oxide synthase oxygenase from Bacillus subtilis (strain 168)

Seq: 363 a.a.

Struc: 362 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.1.14.14.47 - nitric-oxide synthase (flavodoxin).
• Reaction: 3 reduced [flavodoxin] + 2 L-arginine + 4 O2 = 3 oxidized [flavodoxin] + 2 L-citrulline + 2 nitric oxide + 4 H2O + 5 H⁺
• Cofactor: 5,6,7,8-tetrahydrobiopterin; Ferriheme b

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm501723p

J Med Chem 58:994 (2015)

PubMed id: 25522110

Structure-based design of bacterial nitric oxide synthase inhibitors.

J.K.Holden, S.Kang, S.A.Hollingsworth, H.Li, N.Lim, S.Chen, H.Huang, F.Xue, W.Tang, R.B.Silverman, T.L.Poulos.

ABSTRACT

Inhibition of bacterial nitric oxide synthase (bNOS) has the potential to improve the efficacy of antimicrobials used to treat infections by Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis. However, inhibitor specificity toward bNOS over the mammalian NOS (mNOS) isoforms remains a challenge because of the near identical NOS active sites. One key structural difference between the NOS isoforms is the amino acid composition of the pterin cofactor binding site that is adjacent to the NOS active site. Previously, we demonstrated that a NOS inhibitor targeting both the active and pterin sites was potent and functioned as an antimicrobial ( Holden , , Proc. Natl. Acad. Sci. U.S.A. 2013 , 110 , 18127 ). Here we present additional crystal structures, binding analyses, and bacterial killing studies of inhibitors that target both the active and pterin sites of a bNOS and function as antimicrobials. Together, these data provide a framework for continued development of bNOS inhibitors, as each molecule represents an excellent chemical scaffold for the design of isoform selective bNOS inhibitors.