2GQ2: Mycobacterium Tuberculosis Thyx-Nadp Complex

Citation:
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.
PDB ID: 2GQ2Download
MMDB ID: 40016
PDB Deposition Date: 2006/4/19
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 2GQ2: tetrameric; determined by author and by software (PISA)
Molecular Components in 2GQ2
Label Count Molecule
Proteins (4 molecules)
4
Thymidylate Synthase Thyx
Molecule annotation
Chemicals (31 molecules)
1
15
2
4
3
4
4
1
5
7
* Click molecule labels to explore molecular sequence information.

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