4CU1

Structure of bovine endothelial nitric oxide synthase heme domain in complex with 6-[(2S)-3-amino-2-{5-[2-(6-amino-4-methylpyridin-2-yl)ethyl]pyridin-3-yl}propyl]-4-methylpyridin-2-amine

Summary for 4CU1

• Entry DOI: 10.2210/pdb4cu1/pdb
• Related: 4CTP 4CTQ 4CTR 4CTT 4CTU 4CTV 4CTW 4CTX 4CTY 4CTZ 4CU0
• Descriptor: NITRIC OXIDE SYNTHASE, ENDOTHELIAL, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (9 entities in total)
• Functional Keywords: oxidoreductase, inhibitor complex
• Biological source: BOS TAURUS (CATTLE); More
• Cellular location: Cell membrane: P29473 P29473
• Total number of polymer chains: 2
• Total formula weight: 102186.19

Authors

Li, H.,Poulos, T.L. (deposition date: 2014-03-15, release date: 2014-05-07, Last modification date: 2024-10-16)

Primary citation

Kang, S.,Tang, W.,Li, H.,Chreifi, G.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Nitric Oxide Synthase Inhibitors that Interact with Both a Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity.
J.Med.Chem., 57:4382-, 2014

PubMed Abstract: Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of α-amino functionalized aminopyridine derivatives (3-8) were designed to probe the structure-activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors.

PubMed: 24758147
DOI: 10.1021/JM5004182

Experimental method

X-RAY DIFFRACTION (1.89 Å)