4D7O

Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(4-(((3-Fluorophenethyl)amino)methyl)phenyl)-4- methylpyridin-2-amine

Summary for 4D7O

• Entry DOI: 10.2210/pdb4d7o/pdb
• Descriptor: NITRIC OXIDE SYNTHASE, BRAIN, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total)
• Functional Keywords: oxidoreductase, nitric oxide synthase, inhibitor complex
• Biological source: RATTUS NORVEGICUS (NORWAY RAT)
• Cellular location: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• Total number of polymer chains: 2
• Total formula weight: 100194.86

Authors

Li, H.,Poulos, T.L. (deposition date: 2014-11-25, release date: 2015-07-01, Last modification date: 2024-05-08)

Primary citation

Holden, J.K.,Kang, S.,Beasley, F.C.,Cinelli, M.A.,Li, H.,Roy, S.G.,Dejam, D.,Edinger, A.L.,Nizet, V.,Silverman, R.B.,Poulos, T.L.
Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus Aureus
Chem.Biol., 22:785-, 2015

PubMed Abstract: Bacterial infections associated with methicillin-resistant Staphylococcus aureus (MRSA) are a major economic burden to hospitals, and confer high rates of morbidity and mortality among those infected. Exploitation of novel therapeutic targets is thus necessary to combat this dangerous pathogen. Here, we report on the identification and characterization, including crystal structures, of two nitric oxide synthase (NOS) inhibitors that function as antimicrobials against MRSA. These data provide the first evidence that bacterial NOS (bNOS) inhibitors can work synergistically with oxidative stress to enhance MRSA killing. Crystal structures show that each inhibitor contacts an active site Ile residue in bNOS that is Val in the mammalian NOS isoforms. Mutagenesis studies show that the additional nonpolar contacts provided by the Ile in bNOS contribute to tighter binding toward the bacterial enzyme.

PubMed: 26091171
DOI: 10.1016/J.CHEMBIOL.2015.05.013

Experimental method

X-RAY DIFFRACTION (1.78 Å)