2GQ2

Mycobacterium tuberculosis ThyX-NADP complex

Summary for 2GQ2

• Entry DOI: 10.2210/pdb2gq2/pdb
• Related: 2AF6
• Descriptor: Thymidylate synthase thyX, IODIDE ION, POTASSIUM ION, ... (7 entities in total)
• Functional Keywords: m.tuberculosis, thyx, fdts, tscp, flavin dependent thymidylate synthase, inhibitor design, bivalent drugs, transferase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 4
• Total formula weight: 121708.31

Authors

Sampathkumar, P.,Turley, S.,Sibley, C.H.,Hol, W.G. (deposition date: 2006-04-19, release date: 2006-06-27, Last modification date: 2024-11-20)

Primary citation

Sampathkumar, P.,Turley, S.,Sibley, C.H.,Hol, W.G.
NADP+ expels both the co-factor and a substrate analog from the Mycobacterium tuberculosis ThyX active site: opportunities for anti-bacterial drug design.
J.Mol.Biol., 360:1-6, 2006

PubMed Abstract: 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.

PubMed: 16730023
DOI: 10.1016/j.jmb.2006.04.061

Experimental method

X-RAY DIFFRACTION (2.1 Å)