2a9w
From Proteopedia
(New page: 200px<br /><applet load="2a9w" size="450" color="white" frame="true" align="right" spinBox="true" caption="2a9w, resolution 1.65Å" /> '''E. coli TS complexed...) |
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| - | [[Image:2a9w.gif|left|200px]]<br /><applet load="2a9w" size=" | + | [[Image:2a9w.gif|left|200px]]<br /><applet load="2a9w" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2a9w, resolution 1.65Å" /> | caption="2a9w, resolution 1.65Å" /> | ||
'''E. coli TS complexed with dUMP and inhibitor GA9'''<br /> | '''E. coli TS complexed with dUMP and inhibitor GA9'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The ternary complex crystal structures of Cryptococcus neoformans and | + | The ternary complex crystal structures of Cryptococcus neoformans and Escherichia coli thymidylate synthase (TS) suggest mechanisms of species-specific inhibition of a highly conserved protein. The 2.1 Angstrom structure of C. neoformans TS cocrystallized with substrate and the cofactor analog CB3717 shows that the binding sites for substrate and cofactor are highly conserved with respect to human TS, but that the structure of the cofactor-binding site of C. neoformans TS is less constrained by surrounding residues. This feature might allow C. neoformans TS to form TS-dUMP-inhibitor complexes with a greater range of antifolates than human TS. 3',3''-Dibromophenol-4-chloro-1,8-naphthalein (GA9) selectively inhibits both E. coli TS and C. neoformans TS (K(i) = 4 microM) over human TS (K(i) >> 245 microM). The E. coli TS-dUMP-GA9 complex is in an open conformation, similar to that of the apoenzyme crystal structure. The GA9-binding site overlaps the binding site of the pABA-glutamyl moiety of the cofactor. The fact that human apoTS can adopt an unusual fold in which the GA9-binding site is disordered may explain the poor affinity of GA9 for the human enzyme. These observations highlight the critical need to incorporate multiple target conformations in any computational attempt to facilitate drug discovery. |
==About this Structure== | ==About this Structure== | ||
| - | 2A9W is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with PO4, UMP, GA9, 2BR, BME and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] Full crystallographic information is available from [http:// | + | 2A9W is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=PO4:'>PO4</scene>, <scene name='pdbligand=UMP:'>UMP</scene>, <scene name='pdbligand=GA9:'>GA9</scene>, <scene name='pdbligand=2BR:'>2BR</scene>, <scene name='pdbligand=BME:'>BME</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 Thymidylate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A9W OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Thymidylate synthase]] | [[Category: Thymidylate synthase]] | ||
| - | [[Category: Anderson, A | + | [[Category: Anderson, A C.]] |
| - | [[Category: Costi, M | + | [[Category: Costi, M P.]] |
[[Category: Ferrari, S.]] | [[Category: Ferrari, S.]] | ||
| - | [[Category: Finer-Moore, J | + | [[Category: Finer-Moore, J S.]] |
[[Category: Krucinski, J.]] | [[Category: Krucinski, J.]] | ||
| - | [[Category: Neil, R | + | [[Category: Neil, R H.O.]] |
| - | [[Category: Stroud, R | + | [[Category: Stroud, R M.]] |
[[Category: 2BR]] | [[Category: 2BR]] | ||
[[Category: BME]] | [[Category: BME]] | ||
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[[Category: protein-inhibitor complex]] | [[Category: protein-inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:25:18 2008'' |
Revision as of 14:25, 21 February 2008
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E. coli TS complexed with dUMP and inhibitor GA9
Overview
The ternary complex crystal structures of Cryptococcus neoformans and Escherichia coli thymidylate synthase (TS) suggest mechanisms of species-specific inhibition of a highly conserved protein. The 2.1 Angstrom structure of C. neoformans TS cocrystallized with substrate and the cofactor analog CB3717 shows that the binding sites for substrate and cofactor are highly conserved with respect to human TS, but that the structure of the cofactor-binding site of C. neoformans TS is less constrained by surrounding residues. This feature might allow C. neoformans TS to form TS-dUMP-inhibitor complexes with a greater range of antifolates than human TS. 3',3-Dibromophenol-4-chloro-1,8-naphthalein (GA9) selectively inhibits both E. coli TS and C. neoformans TS (K(i) = 4 microM) over human TS (K(i) >> 245 microM). The E. coli TS-dUMP-GA9 complex is in an open conformation, similar to that of the apoenzyme crystal structure. The GA9-binding site overlaps the binding site of the pABA-glutamyl moiety of the cofactor. The fact that human apoTS can adopt an unusual fold in which the GA9-binding site is disordered may explain the poor affinity of GA9 for the human enzyme. These observations highlight the critical need to incorporate multiple target conformations in any computational attempt to facilitate drug discovery.
About this Structure
2A9W is a Single protein structure of sequence from Escherichia coli with , , , , and as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Full crystallographic information is available from OCA.
Reference
The structure of Cryptococcus neoformans thymidylate synthase suggests strategies for using target dynamics for species-specific inhibition., Finer-Moore JS, Anderson AC, O'Neil RH, Costi MP, Ferrari S, Krucinski J, Stroud RM, Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1320-34. Epub 2005, Sep 28. PMID:16204883
Page seeded by OCA on Thu Feb 21 16:25:18 2008
Categories: Escherichia coli | Single protein | Thymidylate synthase | Anderson, A C. | Costi, M P. | Ferrari, S. | Finer-Moore, J S. | Krucinski, J. | Neil, R H.O. | Stroud, R M. | 2BR | BME | GA9 | GOL | PO4 | UMP | Protein-inhibitor complex
