3cog

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{{STRUCTURE_3cog| PDB=3cog | SCENE= }}
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==Crystal structure of human cystathionase (Cystathionine gamma lyase) in complex with DL-propargylglycine==
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===Crystal structure of human cystathionase (Cystathionine gamma lyase) in complex with DL-propargylglycine===
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<StructureSection load='3cog' size='340' side='right' caption='[[3cog]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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{{ABSTRACT_PUBMED_19019829}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3cog]] is a 4 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=3COG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3COG FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2AG:(2S)-2-AMINOPENT-4-ENOIC+ACID'>2AG</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2nmp|2nmp]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cystathionine_gamma-lyase Cystathionine gamma-lyase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.4.1.1 4.4.1.1] </span></td></tr>
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<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=3cog FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cog OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3cog RCSB], [http://www.ebi.ac.uk/pdbsum/3cog PDBsum]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/CGL_HUMAN CGL_HUMAN]] Defects in CTH are the cause of cystathioninuria (CSTNU) [MIM:[http://omim.org/entry/219500 219500]]. It is an autosomal recessive phenotype characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion.<ref>PMID:18476726</ref> <ref>PMID:12574942</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/CGL_HUMAN CGL_HUMAN]] Catalyzes the last step in the trans-sulfuration pathway from methionine to cysteine. Has broad substrate specificity. Converts cystathionine to cysteine, ammonia and 2-oxobutanoate. Converts two cysteine molecules to lanthionine and hydrogen sulfide. Can also accept homocysteine as substrate. Specificity depends on the levels of the endogenous substrates. Generates the endogenous signaling molecule hydrogen sulfide (H2S), and so contributes to the regulation of blood pressure. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function.<ref>PMID:19261609</ref> <ref>PMID:22169477</ref> <ref>PMID:19019829</ref>
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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/co/3cog_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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Impairment of the formation or action of hydrogen sulfide (H(2)S), an endogenous gasotransmitter, is associated with various diseases, such as hypertension, diabetes mellitus, septic and hemorrhagic shock, and pancreatitis. Cystathionine beta-synthase and cystathionine gamma-lyase (CSE) are two pyridoxal-5'-phosphate (PLP)-dependent enzymes largely responsible for the production of H(2)S in mammals. Inhibition of CSE by DL-propargylglycine (PAG) has been shown to alleviate disease symptoms. Here we report crystal structures of human CSE (hCSE), in apo form, and in complex with PLP and PLP.PAG. Structural characterization, combined with biophysical and biochemical studies, provides new insights into the inhibition mechanism of hCSE-mediated production of H(2)S. Transition from the open form of apo-hCSE to the closed PLP-bound form reveals large conformational changes hitherto not reported. In addition, PAG binds hCSE via a unique binding mode, not observed in PAG-enzyme complexes previously. The interaction of PAG-hCSE was not predicted based on existing information from known PAG complexes. The structure of hCSE.PLP.PAG complex highlights the particular importance of Tyr(114) in hCSE and the mechanism of PAG-dependent inhibition of hCSE. These results provide significant insights, which will facilitate the structure-based design of novel inhibitors of hCSE to aid in the development of therapies for diseases involving disorders of sulfur metabolism.
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==Disease==
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Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S.,Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan CH, van-den-Berg S, Deng LW, Moore PK, Karlberg T, Sivaraman J J Biol Chem. 2009 Jan 30;284(5):3076-85. Epub 2008 Nov 19. PMID:19019829<ref>PMID:19019829</ref>
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[[http://www.uniprot.org/uniprot/CGL_HUMAN CGL_HUMAN]] Defects in CTH are the cause of cystathioninuria (CSTNU) [MIM:[http://omim.org/entry/219500 219500]]. It is an autosomal recessive phenotype characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion.<ref>PMID:18476726</ref><ref>PMID:12574942</ref>
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://www.uniprot.org/uniprot/CGL_HUMAN CGL_HUMAN]] Catalyzes the last step in the trans-sulfuration pathway from methionine to cysteine. Has broad substrate specificity. Converts cystathionine to cysteine, ammonia and 2-oxobutanoate. Converts two cysteine molecules to lanthionine and hydrogen sulfide. Can also accept homocysteine as substrate. Specificity depends on the levels of the endogenous substrates. Generates the endogenous signaling molecule hydrogen sulfide (H2S), and so contributes to the regulation of blood pressure. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function.<ref>PMID:19261609</ref><ref>PMID:22169477</ref><ref>PMID:19019829</ref>
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</div>
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== References ==
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==About this Structure==
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<references/>
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[[3cog]] is a 4 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=3COG OCA].
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__TOC__
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</StructureSection>
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==Reference==
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<ref group="xtra">PMID:019019829</ref><references group="xtra"/><references/>
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[[Category: Cystathionine gamma-lyase]]
[[Category: Cystathionine gamma-lyase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Arrowsmith, C H.]]
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[[Category: Arrowsmith, C H]]
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[[Category: Berg, S Van den.]]
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[[Category: Berg, S Van den]]
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[[Category: Berglund, H.]]
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[[Category: Berglund, H]]
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[[Category: Busam, R D.]]
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[[Category: Busam, R D]]
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[[Category: Collins, R.]]
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[[Category: Collins, R]]
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[[Category: Dahlgren, L G.]]
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[[Category: Dahlgren, L G]]
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[[Category: Edwards, A M.]]
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[[Category: Edwards, A M]]
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[[Category: Flodin, S.]]
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[[Category: Flodin, S]]
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[[Category: Flores, A.]]
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[[Category: Flores, A]]
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[[Category: Graslund, S.]]
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[[Category: Graslund, S]]
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[[Category: Hammarstrom, M.]]
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[[Category: Hammarstrom, M]]
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[[Category: Johansson, I.]]
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[[Category: Johansson, I]]
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[[Category: Kallas, A.]]
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[[Category: Kallas, A]]
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[[Category: Karlberg, T.]]
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[[Category: Karlberg, T]]
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[[Category: Kotenyova, T.]]
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[[Category: Kotenyova, T]]
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[[Category: Lehtio, L.]]
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[[Category: Lehtio, L]]
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[[Category: Moche, M.]]
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[[Category: Moche, M]]
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[[Category: Nilsson, M E.]]
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[[Category: Nilsson, M E]]
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[[Category: Nordlund, P.]]
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[[Category: Nordlund, P]]
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[[Category: Nyman, T.]]
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[[Category: Nyman, T]]
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[[Category: Olesen, K.]]
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[[Category: Olesen, K]]
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[[Category: Persson, C.]]
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[[Category: Persson, C]]
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[[Category: SGC, Structural Genomics Consortium.]]
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[[Category: Structural genomic]]
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[[Category: Sagermark, J.]]
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[[Category: Sagermark, J]]
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[[Category: Schuler, H.]]
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[[Category: Schuler, H]]
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[[Category: Svensson, L.]]
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[[Category: Svensson, L]]
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[[Category: Thorsell, A G.]]
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[[Category: Thorsell, A G]]
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[[Category: Tresaugues, L.]]
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[[Category: Tresaugues, L]]
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[[Category: Weigelt, J.]]
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[[Category: Weigelt, J]]
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[[Category: Welin, M.]]
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[[Category: Welin, M]]
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[[Category: Wikstrom, M.]]
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[[Category: Wikstrom, M]]
[[Category: Amino-acid biosynthesis]]
[[Category: Amino-acid biosynthesis]]
[[Category: Cth]]
[[Category: Cth]]
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[[Category: Sgc]]
[[Category: Sgc]]
[[Category: Sgc stockholm]]
[[Category: Sgc stockholm]]
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[[Category: Structural genomic]]
 
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[[Category: Structural genomics consortium]]
 

Revision as of 13:43, 18 December 2014

Crystal structure of human cystathionase (Cystathionine gamma lyase) in complex with DL-propargylglycine

3cog, resolution 2.00Å

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