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1s2c

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(New page: 200px<br /> <applet load="1s2c" size="450" color="white" frame="true" align="right" spinBox="true" caption="1s2c, resolution 1.80&Aring;" /> '''Crystal structures ...)
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Revision as of 17:03, 12 November 2007

Image:1s2c.gif

1s2c, resolution 1.80Å

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Crystal structures of prostaglandin D2 11-ketoreductase in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin

Overview

It is becoming increasingly well established that nonsteroidal, anti-inflammatory drugs (NSAID) protect against tumors of the, gastrointestinal tract and that they may also protect against a variety of, other tumors. These activities have been widely attributed to the, inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved., Besides targeting COX, certain NSAID also inhibit enzymes belonging to the, aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated, previously that overexpression of AKR1C3 acts to suppress cell, differentiation and promote proliferation in myeloid cells. However, this, enzyme has a broad tissue distribution and therefore represents a novel, candidate for the target of the COX-independent antineoplastic actions of, NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed, with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A, resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin, loop, at the opposite end of the central beta-barrel. Two other crystal, structures (1.20 and 2.1 A resolution) show acetate bound in the active, site occupying the proposed oxyanion hole. The data underline AKR1C3 as a, COX-independent target for NSAID and will provide a structural basis for, the future development of new cancer therapies with reduced COX-dependent, side effects.

About this Structure

1S2C is a Single protein structure of sequence from Homo sapiens with NAP, FLF and DMS as ligands. Full crystallographic information is available from OCA.

Reference

Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin., Lovering AL, Ride JP, Bunce CM, Desmond JC, Cummings SM, White SA, Cancer Res. 2004 Mar 1;64(5):1802-10. PMID:14996743

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