2r42

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{{STRUCTURE_2r42| PDB=2r42 | SCENE= }}
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==The Biochemical and Structural Basis for feedback Inhibition of Mevalonate Kinase and Isoprenoid Metabolism==
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===The Biochemical and Structural Basis for feedback Inhibition of Mevalonate Kinase and Isoprenoid Metabolism===
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<StructureSection load='2r42' size='340' side='right' caption='[[2r42]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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{{ABSTRACT_PUBMED_18302342}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2r42]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R42 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R42 FirstGlance]. <br>
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==Disease==
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FPS:S-[(2E,6E)-3,7,11-TRIMETHYLDODECA-2,6,10-TRIENYL]+TRIHYDROGEN+THIODIPHOSPHATE'>FPS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene><br>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r3v|2r3v]]</td></tr>
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<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Mvk ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus])</td></tr>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mevalonate_kinase Mevalonate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.36 2.7.1.36] </span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r42 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r42 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2r42 RCSB], [http://www.ebi.ac.uk/pdbsum/2r42 PDBsum]</span></td></tr>
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<table>
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== Disease ==
[[http://www.uniprot.org/uniprot/KIME_RAT KIME_RAT]] Note=Mutation in the mevalonate kinase gene causes mevalonicaciduria.
[[http://www.uniprot.org/uniprot/KIME_RAT KIME_RAT]] Note=Mutation in the mevalonate kinase gene causes mevalonicaciduria.
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== Function ==
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==Function==
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[[http://www.uniprot.org/uniprot/KIME_RAT KIME_RAT]] May be a regulatory site in cholesterol biosynthetic pathway.
[[http://www.uniprot.org/uniprot/KIME_RAT KIME_RAT]] May be a regulatory site in cholesterol biosynthetic pathway.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r42_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Mevalonate kinase (MK), which catalyzes a key reaction in polyisoprenoid and sterol metabolism in many organisms, is subject to feedback regulation by farnesyl diphosphate and related compounds. The structures of human mevalonate kinase and a binary complex of the rat enzyme incubated with farnesyl thiodiphosphate (FSPP) are reported. Significant FSPP hydrolysis occurs under crystallization conditions; this results in detection of farnesyl thiophosphate (FSP) in the structure of the binary complex. Farnesyl thiodiphosphate competes with substrate ATP to produce feedback inhibition of mevalonate kinase. The binding sites for these metabolites overlap, with the phosphate of FSP nearly superimposed on ATP's beta-phosphate and FSP's polyisoprenoid chain overlapping ATP's adenosine moiety. Several hydrophobic amino acid side chains are positioned near the polyisoprenoid chain of FSP and their functional significance has been evaluated in mutagenesis experiments with human MK, which exhibits the highest reported sensitivity to feedback inhibition. Results suggest that single and double mutations at T104 and I196 produce a significant inflation of the K(i) for FSPP (approximately 40-fold for T104A/I196A). Such an effect persists when K(i) values are normalized for effects on the K(m) for ATP, suggesting that it may be possible to engineer MK proteins with altered sensitivity to feedback inhibition. Comparison of animal MK protein alignments and structures with those of a MK protein from Streptococcus pneumoniae indicates that sequence differences between N- and C-terminal domains correlate with differences in interdomain angles. Bacterial MK proteins exhibit more solvent exposure of feedback inhibitor binding sites and, consequently, weaker binding of these inhibitors.
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==About this Structure==
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Biochemical and structural basis for feedback inhibition of mevalonate kinase and isoprenoid metabolism.,Fu Z, Voynova NE, Herdendorf TJ, Miziorko HM, Kim JJ Biochemistry. 2008 Mar 25;47(12):3715-24. Epub 2008 Feb 27. PMID:18302342<ref>PMID:18302342</ref>
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[[2r42]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R42 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<ref group="xtra">PMID:018302342</ref><references group="xtra"/><references/>
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</div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Mevalonate kinase]]
[[Category: Mevalonate kinase]]
[[Category: Rattus norvegicus]]
[[Category: Rattus norvegicus]]

Revision as of 19:09, 30 September 2014

The Biochemical and Structural Basis for feedback Inhibition of Mevalonate Kinase and Isoprenoid Metabolism

2r42, resolution 2.40Å

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