5AGN
Structure of rat neuronal nitric oxide synthase heme domain in complex with (S)-2-Amino-5-(2-hydroxyacetimidamido)pentanoic acid
Summary for 5AGN
| Entry DOI | 10.2210/pdb5agn/pdb |
| Related | 5AGK 5AGL 5AGM 5AGO 5AGP |
| 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 | 99902.44 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2015-02-02, release date: 2015-04-29, Last modification date: 2024-05-08) |
| Primary citation | Tang, W.,Li, H.,Doud, E.H.,Chen, Y.,Choing, S.,Plaza, C.,Kelleher, N.L.,Poulos, T.L.,Silverman, R.B. Mechanism of Inactivation of Neuronal Nitric Oxide Synthase by (S)-2-Amino-5-(2-(Methylthio)Acetimidamido)Pentanoic Acid. J.Am.Chem.Soc., 137:5980-, 2015 Cited by PubMed Abstract: Nitric oxide synthase (NOS) catalyzes the conversion of l-arginine to l-citrulline and the second messenger nitric oxide. Three mechanistic pathways are proposed for the inactivation of neuronal NOS (nNOS) by (S)-2-amino-5-(2-(methylthio)acetimidamido)pentanoic acid (1): sulfide oxidation, oxidative dethiolation, and oxidative demethylation. Four possible intermediates were synthesized. All compounds were assayed with nNOS, their IC50, KI, and kinact values were obtained, and their crystal structures were determined. The identification and characterization of the products formed during inactivation provide evidence for the details of the inactivation mechanism. On the basis of these studies, the most probable mechanism for the inactivation of nNOS involves oxidative demethylation with the resulting thiol coordinating to the cofactor heme iron. Although nNOS is a heme-containing enzyme, this is the first example of a NOS that catalyzes an S-demethylation reaction; the novel mechanism of inactivation described here could be applied to the design of inactivators of other heme-dependent enzymes. PubMed: 25874809DOI: 10.1021/JACS.5B01202 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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