1mrs
From Proteopedia
(New page: 200px<br /><applet load="1mrs" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mrs, resolution 2.00Å" /> '''CRYSTAL STRUCTURE OF...) |
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| - | [[Image:1mrs.gif|left|200px]]<br /><applet load="1mrs" size=" | + | [[Image:1mrs.gif|left|200px]]<br /><applet load="1mrs" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1mrs, resolution 2.00Å" /> | caption="1mrs, resolution 2.00Å" /> | ||
'''CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS THYMIDYLATE KINASE COMPLEXED WITH 5-CH2OH DEOXYURIDINE MONOPHOSPHATE'''<br /> | '''CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS THYMIDYLATE KINASE COMPLEXED WITH 5-CH2OH DEOXYURIDINE MONOPHOSPHATE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The chemical synthesis of new compounds designed as inhibitors of | + | The chemical synthesis of new compounds designed as inhibitors of Mycobacterium tuberculosis TMP kinase (TMPK) is reported. The synthesis concerns TMP analogues modified at the 5-position of the thymine ring as well as a novel compound with a six-membered sugar ring. The binding properties of the analogues are compared with the known inhibitor azido-TMP, which is postulated here to work by excluding the TMP-bound Mg(2+) ion. The crystallographic structure of the complex of one of the compounds, 5-CH(2)OH-dUMP, with TMPK has been determined at 2.0 A. It reveals a major conformation for the hydroxyl group in contact with a water molecule and a minor conformation pointing toward Ser(99). Looking for a role for Ser(99), we have identified an unusual catalytic triad, or a proton wire, made of strictly conserved residues (including Glu(6), Ser(99), Arg(95), and Asp(9)) that probably serves to protonate the transferred PO(3) group. The crystallographic structure of the commercially available bisubstrate analogue P(1)-(adenosine-5')-P(5)-(thymidine-5')-pentaphosphate bound to TMPK is also reported at 2.45 A and reveals an alternative binding pocket for the adenine moiety of the molecule compared with what is observed either in the Escherichia coli or in the yeast enzyme structures. This alternative binding pocket opens a way for the design of a new family of specific inhibitors. |
==About this Structure== | ==About this Structure== | ||
| - | 1MRS 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 SO4, MG and 5HU as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/dTMP_kinase dTMP kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.9 2.7.4.9] Full crystallographic information is available from [http:// | + | 1MRS 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=SO4:'>SO4</scene>, <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=5HU:'>5HU</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/dTMP_kinase dTMP kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.9 2.7.4.9] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MRS OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: dTMP kinase]] | [[Category: dTMP kinase]] | ||
| - | [[Category: Calenbergh, S | + | [[Category: Calenbergh, S Van.]] |
[[Category: Delarue, M.]] | [[Category: Delarue, M.]] | ||
[[Category: Froeyen, M.]] | [[Category: Froeyen, M.]] | ||
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[[Category: transferase (atp:tmp phosphotransferase)]] | [[Category: transferase (atp:tmp phosphotransferase)]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:58:22 2008'' |
Revision as of 11:58, 21 February 2008
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CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS THYMIDYLATE KINASE COMPLEXED WITH 5-CH2OH DEOXYURIDINE MONOPHOSPHATE
Overview
The chemical synthesis of new compounds designed as inhibitors of Mycobacterium tuberculosis TMP kinase (TMPK) is reported. The synthesis concerns TMP analogues modified at the 5-position of the thymine ring as well as a novel compound with a six-membered sugar ring. The binding properties of the analogues are compared with the known inhibitor azido-TMP, which is postulated here to work by excluding the TMP-bound Mg(2+) ion. The crystallographic structure of the complex of one of the compounds, 5-CH(2)OH-dUMP, with TMPK has been determined at 2.0 A. It reveals a major conformation for the hydroxyl group in contact with a water molecule and a minor conformation pointing toward Ser(99). Looking for a role for Ser(99), we have identified an unusual catalytic triad, or a proton wire, made of strictly conserved residues (including Glu(6), Ser(99), Arg(95), and Asp(9)) that probably serves to protonate the transferred PO(3) group. The crystallographic structure of the commercially available bisubstrate analogue P(1)-(adenosine-5')-P(5)-(thymidine-5')-pentaphosphate bound to TMPK is also reported at 2.45 A and reveals an alternative binding pocket for the adenine moiety of the molecule compared with what is observed either in the Escherichia coli or in the yeast enzyme structures. This alternative binding pocket opens a way for the design of a new family of specific inhibitors.
About this Structure
1MRS is a Single protein structure of sequence from Mycobacterium tuberculosis with , and as ligands. Active as dTMP kinase, with EC number 2.7.4.9 Full crystallographic information is available from OCA.
Reference
Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism., Haouz A, Vanheusden V, Munier-Lehmann H, Froeyen M, Herdewijn P, Van Calenbergh S, Delarue M, J Biol Chem. 2003 Feb 14;278(7):4963-71. Epub 2002 Nov 25. PMID:12454011
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