3hxt: Difference between revisions
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==Structure of human MTHFS== | |||
=== | <StructureSection load='3hxt' size='340' side='right' caption='[[3hxt]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3hxt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HXT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3HXT FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3hy3|3hy3]], [[3hy4|3hy4]], [[3hy6|3hy6]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MTHFS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/5-formyltetrahydrofolate_cyclo-ligase 5-formyltetrahydrofolate cyclo-ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.3.2 6.3.3.2] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3hxt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hxt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3hxt RCSB], [http://www.ebi.ac.uk/pdbsum/3hxt PDBsum]</span></td></tr> | |||
</table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hx/3hxt_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</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]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
5,10-Methenyltetrahydrofolate synthetase (MTHFS) regulates the flow of carbon through the one-carbon metabolic network, which supplies essential components for the growth and proliferation of cells. Inhibition of MTHFS in human MCF-7 breast cancer cells has been shown to arrest the growth of cells. Absence of the three-dimensional structure of human MTHFS (hMTHFS) has hampered the rational design and optimization of drug candidates. Here, we report the structures of native hMTHFS, a binary complex of hMTHFS with ADP, hMTHFS bound with the N5-iminium phosphate reaction intermediate, and an enzyme-product complex of hMTHFS. The N5-iminium phosphate captured for the first time in our crystal structure unravels a unique strategy used by hMTHFS for recognition of the substrate and provides structural basis for the regulation of enzyme activity. Binding of N10-substituted folate analogues places Y152 in the middle of the channel connecting ATP binding site with the substrate binding pocket, precluding the positioning of gamma-phosphate for a nucleophilic attack. Using the structures of hMTHFS as a guide, we have probed the role of residues surrounding the active site in catalysis by mutagenesis. The ensemble of hMTHFS structures and the mutagenesis data yield a coherent picture of the MTHFS active site, determinants of substrate specificity, and new insights into the mechanism of inhibition of hMTHFS. | |||
Structural basis for the inhibition of human 5,10-methenyltetrahydrofolate synthetase by N10-substituted folate analogues.,Wu D, Li Y, Song G, Cheng C, Zhang R, Joachimiak A, Shaw N, Liu ZJ Cancer Res. 2009 Sep 15;69(18):7294-301. Epub 2009 Sep 8. PMID:19738041<ref>PMID:19738041</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
< | </div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: 5-formyltetrahydrofolate cyclo-ligase]] | [[Category: 5-formyltetrahydrofolate cyclo-ligase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Cheng, C | [[Category: Cheng, C]] | ||
[[Category: Joachimiak, A | [[Category: Joachimiak, A]] | ||
[[Category: Li, Y | [[Category: Li, Y]] | ||
[[Category: Liu, Z J | [[Category: Liu, Z J]] | ||
[[Category: Shaw, N | [[Category: Shaw, N]] | ||
[[Category: Song, G | [[Category: Song, G]] | ||
[[Category: Wu, D | [[Category: Wu, D]] | ||
[[Category: Zhang, R | [[Category: Zhang, R]] | ||
[[Category: Antifolate]] | [[Category: Antifolate]] | ||
[[Category: Atp-binding]] | [[Category: Atp-binding]] | ||