1smc: Difference between revisions
New page: left|200px<br /><applet load="1smc" size="450" color="white" frame="true" align="right" spinBox="true" caption="1smc, resolution 2.10Å" /> '''Mycobacterium tuberc... |
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[[Image:1smc.gif|left|200px]]<br /><applet load="1smc" size=" | [[Image:1smc.gif|left|200px]]<br /><applet load="1smc" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1smc, resolution 2.10Å" /> | caption="1smc, resolution 2.10Å" /> | ||
'''Mycobacterium tuberculosis dUTPase complexed with dUTP in the absence of metal ion.'''<br /> | '''Mycobacterium tuberculosis dUTPase complexed with dUTP in the absence of metal ion.'''<br /> | ||
==Overview== | ==Overview== | ||
The structure of Mycobacterium tuberculosis dUTP nucleotidohydrolase | The structure of Mycobacterium tuberculosis dUTP nucleotidohydrolase (dUTPase) has been determined at 1.3 Angstrom resolution in complex with magnesium ion and the non-hydrolyzable substrate analog, alpha,beta-imido dUTP. dUTPase is an enzyme essential for depleting potentially toxic concentrations of dUTP in the cell. Given the importance of its biological role, it has been proposed that inhibiting M.tuberculosis dUTPase might be an effective means to treat tuberculosis infection in humans. The crystal structure presented here offers some insight into the potential for designing a specific inhibitor of the M.tuberculosis dUTPase enzyme. The structure also offers new insights into the mechanism of dUTP hydrolysis by providing an accurate representation of the enzyme-substrate complex in which both the metal ion and dUTP analog are included. The structure suggests that inclusion of a magnesium ion is important for stabilizing the position of the alpha-phosphorus for an in-line nucleophilic attack. In the absence of magnesium, the alpha-phosphate of dUTP can have either of the two positions which differ by 4.5 Angstrom. A transiently ordered C-terminal loop further assists catalysis by shielding the general base, Asp83, from solvent thus elevating its pK(a) so that it might in turn activate a tightly bound water molecule for nucleophilic attack. The metal ion coordinates alpha, beta, and gamma phosphate groups with tridentate geometry identical with that observed in the crystal structure of DNA polymerase beta complexed with magnesium and dNTP analog, revealing some common features in catalytic mechanism. | ||
==About this Structure== | ==About this Structure== | ||
1SMC 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 NO3, DUT and TRS as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/dUTP_diphosphatase dUTP diphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.23 3.6.1.23] Full crystallographic information is available from [http:// | 1SMC 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=NO3:'>NO3</scene>, <scene name='pdbligand=DUT:'>DUT</scene> and <scene name='pdbligand=TRS:'>TRS</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/dUTP_diphosphatase dUTP diphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.23 3.6.1.23] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SMC OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Cascio, D.]] | [[Category: Cascio, D.]] | ||
[[Category: Chan, S.]] | [[Category: Chan, S.]] | ||
[[Category: Cho, U | [[Category: Cho, U S.]] | ||
[[Category: Eisenberg, D.]] | [[Category: Eisenberg, D.]] | ||
[[Category: Kim, C | [[Category: Kim, C Y.]] | ||
[[Category: Kim, M | [[Category: Kim, M Y.]] | ||
[[Category: Krupka, H.]] | [[Category: Krupka, H.]] | ||
[[Category: Lekin, T.]] | [[Category: Lekin, T.]] | ||
[[Category: Naranjo, C | [[Category: Naranjo, C M.]] | ||
[[Category: Park, M | [[Category: Park, M S.]] | ||
[[Category: Pashkov, I.]] | [[Category: Pashkov, I.]] | ||
[[Category: Perry, J | [[Category: Perry, J L.]] | ||
[[Category: Rogers, Y | [[Category: Rogers, Y C.]] | ||
[[Category: Sawaya, M | [[Category: Sawaya, M R.]] | ||
[[Category: Segelke, B.]] | [[Category: Segelke, B.]] | ||
[[Category: So, M.]] | [[Category: So, M.]] | ||
[[Category: TBSGC, TB | [[Category: TBSGC, TB Structural Genomics Consortium.]] | ||
[[Category: Terwilliger, T | [[Category: Terwilliger, T C.]] | ||
[[Category: Waldo, G | [[Category: Waldo, G S.]] | ||
[[Category: Yeates, T | [[Category: Yeates, T O.]] | ||
[[Category: DUT]] | [[Category: DUT]] | ||
[[Category: NO3]] | [[Category: NO3]] | ||
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[[Category: tbsgc]] | [[Category: tbsgc]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:02:58 2008'' | ||
Revision as of 16:03, 21 February 2008
|
Mycobacterium tuberculosis dUTPase complexed with dUTP in the absence of metal ion.
OverviewOverview
The structure of Mycobacterium tuberculosis dUTP nucleotidohydrolase (dUTPase) has been determined at 1.3 Angstrom resolution in complex with magnesium ion and the non-hydrolyzable substrate analog, alpha,beta-imido dUTP. dUTPase is an enzyme essential for depleting potentially toxic concentrations of dUTP in the cell. Given the importance of its biological role, it has been proposed that inhibiting M.tuberculosis dUTPase might be an effective means to treat tuberculosis infection in humans. The crystal structure presented here offers some insight into the potential for designing a specific inhibitor of the M.tuberculosis dUTPase enzyme. The structure also offers new insights into the mechanism of dUTP hydrolysis by providing an accurate representation of the enzyme-substrate complex in which both the metal ion and dUTP analog are included. The structure suggests that inclusion of a magnesium ion is important for stabilizing the position of the alpha-phosphorus for an in-line nucleophilic attack. In the absence of magnesium, the alpha-phosphate of dUTP can have either of the two positions which differ by 4.5 Angstrom. A transiently ordered C-terminal loop further assists catalysis by shielding the general base, Asp83, from solvent thus elevating its pK(a) so that it might in turn activate a tightly bound water molecule for nucleophilic attack. The metal ion coordinates alpha, beta, and gamma phosphate groups with tridentate geometry identical with that observed in the crystal structure of DNA polymerase beta complexed with magnesium and dNTP analog, revealing some common features in catalytic mechanism.
About this StructureAbout this Structure
1SMC is a Single protein structure of sequence from Mycobacterium tuberculosis with , and as ligands. Active as dUTP diphosphatase, with EC number 3.6.1.23 Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of the Mycobacterium tuberculosis dUTPase: insights into the catalytic mechanism., Chan S, Segelke B, Lekin T, Krupka H, Cho US, Kim MY, So M, Kim CY, Naranjo CM, Rogers YC, Park MS, Waldo GS, Pashkov I, Cascio D, Perry JL, Sawaya MR, J Mol Biol. 2004 Aug 6;341(2):503-17. PMID:15276840
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Mycobacterium tuberculosis
- Single protein
- DUTP diphosphatase
- Cascio, D.
- Chan, S.
- Cho, U S.
- Eisenberg, D.
- Kim, C Y.
- Kim, M Y.
- Krupka, H.
- Lekin, T.
- Naranjo, C M.
- Park, M S.
- Pashkov, I.
- Perry, J L.
- Rogers, Y C.
- Sawaya, M R.
- Segelke, B.
- So, M.
- TBSGC, TB Structural Genomics Consortium.
- Terwilliger, T C.
- Waldo, G S.
- Yeates, T O.
- DUT
- NO3
- TRS
- Jelly-roll
- Protein structure initiative
- Psi
- Structural genomics
- Tb structural genomics consortium
- Tbsgc