3N5X

Structure of neuronal nitric oxide synthase heme domain in complex with 4-(2-(5-(2-(6-amino-4-methylpyridin-2-yl)ethyl)pyridin-3-yl)ethyl)-6-methylpyridin-2-amine

Summary for 3N5X

• Entry DOI: 10.2210/pdb3n5x/pdb
• Related: 3N5P 3N5Q 3N5R 3N5S 3N5T 3N5V 3N5W 3N5Y 3N5Z 3N60 3N61 3N62 3N63 3N64 3N65 3N66 3N67 3N68 3N69 3N6A 3N6B 3N6C 3N6D 3N6E 3N6F 3N6G
• Descriptor: Nitric oxide synthase, PROTOPORPHYRIN IX CONTAINING FE, 6-(2-{5-[2-(2-amino-6-methylpyridin-4-yl)ethyl]pyridin-3-yl}ethyl)-4-methylpyridin-2-amine, ... (7 entities in total)
• Functional Keywords: heme enzyme, nitric oxide synthase, substrate inhibitor, zn binding', oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Rattus norvegicus (rat)
• Total number of polymer chains: 2
• Total formula weight: 100633.08

Authors

Li, H.,Delker, S.L.,Poulos, T.L. (deposition date: 2010-05-25, release date: 2011-02-09, Last modification date: 2023-09-06)

Primary citation

Delker, S.L.,Xue, F.,Li, H.,Jamal, J.,Silverman, R.B.,Poulos, T.L.
Role of zinc in isoform-selective inhibitor binding to neuronal nitric oxide synthase .
Biochemistry, 49:10803-10810, 2010

PubMed Abstract: In previous studies [Delker, S. L., et al. (2010), J. Am. Chem. Soc. 132, 5437-5442], we determined the crystal structures of neuronal nitric oxide synthase (nNOS) in complex with nNOS-selective chiral pyrrolidine inhibitors, designed to have an aminopyridine group bound over the heme where it can electrostatically interact with the conserved active site Glu residue. However, in addition to the expected binding mode with the (S,S)-cis inhibitors, an unexpected "flipped" orientation was observed for the (R,R)-cis enantiomers. In the flipped mode, the aminopyridine extends out of the active site where it interacts with one heme propionate. This prompted us to design and synthesize symmetric "double-headed" inhibitors with an aminopyridine at each end of a bridging ring structure [Xue, F., Delker, S. L., Li, H., Fang, J., Jamal, J., Martásek, P., Roman, L. J., Poulos, T. L., and Silverman, R. B. Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase. J. Med. Chem. (submitted for publication)]. One aminopyridine should interact with the active site Glu and the other with the heme propionate. Crystal structures of these double-headed aminopyridine inhibitors in complexes with nNOS show unexpected and significant protein and heme conformational changes induced by inhibitor binding that result in removal of the tetrahydrobiopterin (H(4)B) cofactor and creation of a new Zn(2+) site. These changes are due to binding of a second inhibitor molecule that results in the displacement of H(4)B and the placement of the inhibitor pyridine group in position to serve as a Zn(2+) ligand together with Asp, His, and a chloride ion. Binding of the second inhibitor molecule and generation of the Zn(2+) site do not occur in eNOS. Structural requirements for creation of the new Zn(2+) site in nNOS were analyzed in detail. These observations open the way for the potential design of novel inhibitors selective for nNOS.

PubMed: 21138269
DOI: 10.1021/bi1013479

Experimental method

X-RAY DIFFRACTION (1.8 Å)