2gq2: Difference between revisions
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'''Mycobacterium tuberculosis ThyX-NADP complex''' | '''Mycobacterium tuberculosis ThyX-NADP complex''' | ||
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[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Hol, W G.]] | [[Category: Hol, W G.]] | ||
[[Category: Sampathkumar, P.]] | [[Category: Sampathkumar, P.]] | ||
[[Category: Sibley, C H.]] | [[Category: Sibley, C H.]] | ||
[[Category: Turley, S.]] | [[Category: Turley, S.]] | ||
[[Category: | [[Category: Bivalent drug]] | ||
[[Category: | [[Category: Fdt]] | ||
[[Category: | [[Category: Flavin dependent thymidylate synthase]] | ||
[[Category: | [[Category: Inhibitor design]] | ||
[[Category: | [[Category: M tuberculosis]] | ||
[[Category: | [[Category: Thyx]] | ||
[[Category: | [[Category: Tscp]] | ||
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Revision as of 02:23, 4 May 2008
Mycobacterium tuberculosis ThyX-NADP complex
Overview
The novel flavin-dependent thymidylate synthase, ThyX, is absent in humans but several pathogenic bacteria depend exclusively on ThyX activity to synthesize thymidylate. Reduction of the enzyme-bound FAD by NADPH is suggested to be the critical first step in ThyX catalysis. We soaked Mycobacterium tuberculosis ThyX-FAD-BrdUMP ternary complex crystals in a solution containing NADP+ to gain structural insights into the reductive step of the catalytic cycle. Surprisingly, the NADP+ displaced both FAD and BrdUMP from the active site. In the resultant ThyX-NADP+ binary complex, the AMP moiety is bound in a deep pocket similar to that of the same moiety of FAD in the ternary complex, while the nicotinamide part of NADP+ is engaged in a limited number of contacts with ThyX. The additional 2'-phosphate group attached to the AMP ribose of NADP+ could be accommodated with minor rearrangement of water molecules. The newly introduced 2'-phosphate groups are engaged in water-mediated interactions across the non-crystallographic 2-fold axis of the ThyX tetramer, suggesting possibilities for design of high-affinity bivalent inhibitors of this intriguing enzyme.
About this Structure
2GQ2 is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.
Reference
NADP+ expels both the co-factor and a substrate analog from the Mycobacterium tuberculosis ThyX active site: opportunities for anti-bacterial drug design., Sampathkumar P, Turley S, Sibley CH, Hol WG, J Mol Biol. 2006 Jun 30;360(1):1-6. Epub 2006 May 12. PMID:16730023 Page seeded by OCA on Sun May 4 05:23:29 2008
