2gq2: Difference between revisions
New page: left|200px<br /><applet load="2gq2" size="450" color="white" frame="true" align="right" spinBox="true" caption="2gq2, resolution 2.10Å" /> '''Mycobacterium tuberc... |
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[[Image:2gq2.gif|left|200px]]<br /><applet load="2gq2" size=" | [[Image:2gq2.gif|left|200px]]<br /><applet load="2gq2" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2gq2, resolution 2.10Å" /> | caption="2gq2, resolution 2.10Å" /> | ||
'''Mycobacterium tuberculosis ThyX-NADP complex'''<br /> | '''Mycobacterium tuberculosis ThyX-NADP complex'''<br /> | ||
==Overview== | ==Overview== | ||
The novel flavin-dependent thymidylate synthase, ThyX, is absent in humans | 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== | ==About this Structure== | ||
2GQ2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with IOD, K, NAP, PGE and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thymidylate_synthase_(FAD) Thymidylate synthase (FAD)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.148 2.1.1.148] Full crystallographic information is available from [http:// | 2GQ2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with <scene name='pdbligand=IOD:'>IOD</scene>, <scene name='pdbligand=K:'>K</scene>, <scene name='pdbligand=NAP:'>NAP</scene>, <scene name='pdbligand=PGE:'>PGE</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thymidylate_synthase_(FAD) Thymidylate synthase (FAD)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.148 2.1.1.148] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GQ2 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Thymidylate synthase (FAD)]] | [[Category: Thymidylate synthase (FAD)]] | ||
[[Category: Hol, W | [[Category: Hol, W G.]] | ||
[[Category: Sampathkumar, P.]] | [[Category: Sampathkumar, P.]] | ||
[[Category: Sibley, C | [[Category: Sibley, C H.]] | ||
[[Category: Turley, S.]] | [[Category: Turley, S.]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
| Line 27: | Line 27: | ||
[[Category: flavin dependent thymidylate synthase]] | [[Category: flavin dependent thymidylate synthase]] | ||
[[Category: inhibitor design]] | [[Category: inhibitor design]] | ||
[[Category: m | [[Category: m tuberculosis]] | ||
[[Category: thyx]] | [[Category: thyx]] | ||
[[Category: tscp]] | [[Category: tscp]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:34:07 2008'' | ||
Revision as of 18:34, 21 February 2008
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Mycobacterium tuberculosis ThyX-NADP complex
OverviewOverview
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 StructureAbout this Structure
2GQ2 is a Single protein structure of sequence from Mycobacterium tuberculosis with , , , and as ligands. Active as Thymidylate synthase (FAD), with EC number 2.1.1.148 Full crystallographic information is available from OCA.
ReferenceReference
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
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