4K5I

Structure of bovine endothelial nitric oxide synthase heme domain in complex with (R)-1,2-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-propan-3-amine

Summary for 4K5I

• Entry DOI: 10.2210/pdb4k5i/pdb
• Related: 4K5D 4K5E 4K5F 4K5G 4K5H 4K5J 4K5K
• Descriptor: Nitric oxide synthase, endothelial, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (8 entities in total)
• Functional Keywords: nitric oxide synthase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Bos taurus (bovine)
• Cellular location: Cell membrane : P29473
• Total number of polymer chains: 2
• Total formula weight: 102318.09

Authors

Li, H.,Poulos, T.L. (deposition date: 2013-04-14, release date: 2013-09-18, Last modification date: 2024-10-16)

Primary citation

Jing, Q.,Li, H.,Chreifi, G.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.
Bioorg.Med.Chem.Lett., 23:5674-5679, 2013

PubMed Abstract: To develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization.

PubMed: 23993333
DOI: 10.1016/j.bmcl.2013.08.034

Experimental method

X-RAY DIFFRACTION (2.08 Å)