4UGK

Structure of Bacillus subtilis Nitric Oxide Synthase in complex with 6-(2-(5-(2-(Dimethylamino)ethyl)pyridin-3-yl)ethyl)-4-methylpyridin-2- amine

Summary for 4UGK

• Entry DOI: 10.2210/pdb4ugk/pdb
• Related: 4UG5 4UG6 4UG7 4UG8 4UG9 4UGA 4UGB 4UGC 4UGD 4UGE 4UGF 4UGG 4UGH 4UGI 4UGJ 4UGL 4UGM 4UGN 4UGO 4UGP 4UGQ 4UGR 4UGS 4UGT 4UGU 4UGV 4UGW 4UGX 4UGY
• Descriptor: NITRIC OXIDE SYNTHASE OXYGENASE, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (6 entities in total)
• Functional Keywords: oxidoreductase, inhibitor
• Biological source: BACILLUS SUBTILIS
• Total number of polymer chains: 1
• Total formula weight: 42964.67

Authors

Holden, J.K.,Poulos, T.L. (deposition date: 2015-03-22, release date: 2015-06-24, Last modification date: 2023-12-20)

Primary citation

Holden, J.K.,Dejam, D.,Lewis, M.C.,Huang, H.,Kang, S.,Jing, Q.,Xue, F.,Silverman, R.B.,Poulos, T.L.
Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase.
Biochemistry, 54:4075-, 2015

PubMed Abstract: Nitric oxide generated by bacterial nitric oxide synthase (NOS) increases the susceptibility of Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis to oxidative stress, including antibiotic-induced oxidative stress. Not surprisingly, NOS inhibitors also improve the effectiveness of antimicrobials. Development of potent and selective bacterial NOS inhibitors is complicated by the high active site sequence and structural conservation shared with the mammalian NOS isoforms. To exploit bacterial NOS for the development of new therapeutics, recognition of alternative NOS surfaces and pharmacophores suitable for drug binding is required. Here, we report on a wide number of inhibitor-bound bacterial NOS crystal structures to identify several compounds that interact with surfaces unique to the bacterial NOS. Although binding studies indicate that these inhibitors weakly interact with the NOS active site, many of the inhibitors reported here provide a revised structural framework for the development of new antimicrobials that target bacterial NOS. In addition, mutagenesis studies reveal several key residues that unlock access to bacterial NOS surfaces that could provide the selectivity required to develop potent bacterial NOS inhibitors.

PubMed: 26062720
DOI: 10.1021/ACS.BIOCHEM.5B00431

Experimental method

X-RAY DIFFRACTION (1.62 Å)