1n5x

From Proteopedia

Xanthine Dehydrogenase from Bovine Milk with Inhibitor TEI-6720 Bound

Overview

TEI-6720 (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic, acid) is an extremely potent inhibitor of xanthine oxidoreductase. Steady, state kinetics measurements exhibit mixed type inhibition with K(i) and, K(i)' values of 1.2 +/- 0.05 x 10(-10) m and 9 +/- 0.05 x 10(-10) m, respectively. Fluorescence-monitored titration experiments showed that, TEI-6720 bound very tightly to both the active and the inactive, desulfo-form of the enzyme. The dissociation constant determined for the, desulfo-form was 2 +/- 0.03 x 10(-9) m; for the active form, the, corresponding number was too low to allow accurate measurements. The, crystal structure of the active sulfo-form of milk xanthine dehydrogenase, complexed with TEI-6720 and determined at 2.8-A resolution revealed the, inhibitor molecule bound in a long, narrow channel leading to the, molybdenum-pterin active site of the enzyme. It filled up most of the, channel and the immediate environment of the cofactor, very effectively, inhibiting the activity of the enzyme through the prevention of substrate, binding. Although the inhibitor did not directly coordinate to the, molybdenum ion, numerous hydrogen bonds as well as hydrophobic, interactions with the protein matrix were observed, most of which are also, used in substrate recognition.

About this Structure

1N5X is a Single protein structure of sequence from Bos taurus with FES, MTE, MOS, FAD and TEI as ligands. Active as Xanthine dehydrogenase, with EC number 1.17.1.4 Full crystallographic information is available from OCA.

Reference

An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition., Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T, J Biol Chem. 2003 Jan 17;278(3):1848-55. Epub 2002 Nov 5. PMID:12421831

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