4D3U

Structure of Bacillus subtilis Nitric Oxide Synthase H128S in complex with N-{3-[(1S)-2-(3-{(Z)-[amino(thiophen-2-yl)methylidene]amino}phenoxy)-1-hydroxyethyl]phenyl}thiophene-2-carboximidamide

Summary for 4D3U

• Entry DOI: 10.2210/pdb4d3u/pdb
• Related: 4D3I 4D3J 4D3K 4D3M 4D3N 4D3O 4D3T 4D3V
• Descriptor: NITRIC OXIDE SYNTHASE OXYGENASE, PROTOPORPHYRIN IX CONTAINING FE, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: oxidoreductase, inhibitor
• Biological source: BACILLUS SUBTILIS SUBSP. SUBTILIS STR. 168
• Total number of polymer chains: 1
• Total formula weight: 43496.29

Authors

Holden, J.K.,Poulos, T.L. (deposition date: 2014-10-23, release date: 2015-01-14, Last modification date: 2023-12-20)

Primary citation

Holden, J.K.,Kang, S.,Hollingsworth, S.A.,Li, H.,Lim, N.,Chen, S.,Huang, H.,Xue, F.,Tang, W.,Silverman, R.B.,Poulos, T.L.
Structure-Based Design of Bacterial Nitric Oxide Synthase Inhibitors.
J.Med.Chem., 58:994-, 2015

PubMed 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.

PubMed: 25522110
DOI: 10.1021/JM501723P

Experimental method

X-RAY DIFFRACTION (1.981 Å)