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2okj

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(New page: 200px<br /> <applet load="2okj" size="450" color="white" frame="true" align="right" spinBox="true" caption="2okj, resolution 2.300&Aring;" /> '''The X-ray crystal ...)
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[[Image:2okj.gif|left|200px]]<br />
 
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<applet load="2okj" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2okj, resolution 2.300&Aring;" />
 
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'''The X-ray crystal structure of the 67kDa isoform of Glutamic Acid Decarboxylase (GAD67)'''<br />
 
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==Overview==
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==The X-ray crystal structure of the 67kDa isoform of Glutamic Acid Decarboxylase (GAD67)==
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Gamma-aminobutyric acid (GABA) is synthesized by two isoforms of the, pyridoxal 5'-phosphate-dependent enzyme glutamic acid decarboxylase (GAD65, and GAD67). GAD67 is constitutively active and is responsible for basal, GABA production. In contrast, GAD65, an autoantigen in type I diabetes, is, transiently activated in response to the demand for extra GABA in, neurotransmission, and cycles between an active holo form and an inactive, apo form. We have determined the crystal structures of N-terminal, truncations of both GAD isoforms. The structure of GAD67 shows a tethered, loop covering the active site, providing a catalytic environment that, sustains GABA production. In contrast, the same catalytic loop is, inherently mobile in GAD65. Kinetic studies suggest that mobility in the, catalytic loop promotes a side reaction that results in cofactor release, and GAD65 autoinactivation. These data reveal the molecular basis for, regulation of GABA homeostasis.
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<StructureSection load='2okj' size='340' side='right'caption='[[2okj]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2okj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OKJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OKJ FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ABU:GAMMA-AMINO-BUTANOIC+ACID'>ABU</scene>, <scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene>, <scene name='pdbligand=PLZ:4-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]BUTANOIC+ACID'>PLZ</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2okj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2okj OCA], [https://pdbe.org/2okj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2okj RCSB], [https://www.ebi.ac.uk/pdbsum/2okj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2okj ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/DCE1_HUMAN DCE1_HUMAN] Defects in GAD1 are the cause of cerebral palsy spastic quadriplegic type 1 (CPSQ1) [MIM:[https://omim.org/entry/603513 603513]. A non-progressive disorder of movement and/or posture resulting from defects in the developing central nervous system. Affected individuals manifest symmetrical, non-progressive spasticity and no adverse perinatal history or obvious underlying alternative diagnosis. Developmental delay, mental retardation and sometimes epilepsy can be part of the clinical picture.<ref>PMID:15571623</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/DCE1_HUMAN DCE1_HUMAN] Catalyzes the production of GABA.
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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/ok/2okj_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/main_output.php?pdb_ID=2okj 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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Gamma-aminobutyric acid (GABA) is synthesized by two isoforms of the pyridoxal 5'-phosphate-dependent enzyme glutamic acid decarboxylase (GAD65 and GAD67). GAD67 is constitutively active and is responsible for basal GABA production. In contrast, GAD65, an autoantigen in type I diabetes, is transiently activated in response to the demand for extra GABA in neurotransmission, and cycles between an active holo form and an inactive apo form. We have determined the crystal structures of N-terminal truncations of both GAD isoforms. The structure of GAD67 shows a tethered loop covering the active site, providing a catalytic environment that sustains GABA production. In contrast, the same catalytic loop is inherently mobile in GAD65. Kinetic studies suggest that mobility in the catalytic loop promotes a side reaction that results in cofactor release and GAD65 autoinactivation. These data reveal the molecular basis for regulation of GABA homeostasis.
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==Disease==
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GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop.,Fenalti G, Law RH, Buckle AM, Langendorf C, Tuck K, Rosado CJ, Faux NG, Mahmood K, Hampe CS, Banga JP, Wilce M, Schmidberger J, Rossjohn J, El-Kabbani O, Pike RN, Smith AI, Mackay IR, Rowley MJ, Whisstock JC Nat Struct Mol Biol. 2007 Apr;14(4):280-6. Epub 2007 Mar 25. PMID:17384644<ref>PMID:17384644</ref>
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Known diseases associated with this structure: Cerebral palsy, spastic, symmetric, autosomal recessive OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605363 605363]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2OKJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ABU and PLZ as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Glutamate_decarboxylase Glutamate decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.15 4.1.1.15] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2OKJ OCA].
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</div>
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<div class="pdbe-citations 2okj" style="background-color:#fffaf0;"></div>
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==Reference==
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== References ==
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GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop., Fenalti G, Law RH, Buckle AM, Langendorf C, Tuck K, Rosado CJ, Faux NG, Mahmood K, Hampe CS, Banga JP, Wilce M, Schmidberger J, Rossjohn J, El-Kabbani O, Pike RN, Smith AI, Mackay IR, Rowley MJ, Whisstock JC, Nat Struct Mol Biol. 2007 Apr;14(4):280-6. Epub 2007 Mar 25. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17384644 17384644]
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<references/>
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[[Category: Glutamate decarboxylase]]
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Buckle, A.M.]]
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[[Category: Buckle AM]]
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[[Category: Fenalti, G.]]
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[[Category: Fenalti G]]
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[[Category: Law, R.H.P.]]
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[[Category: Law RHP]]
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[[Category: Whisstock, J.C.]]
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[[Category: Whisstock JC]]
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[[Category: ABU]]
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[[Category: PLZ]]
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[[Category: plp-dependent decarboxylase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:12:32 2007''
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Current revision

The X-ray crystal structure of the 67kDa isoform of Glutamic Acid Decarboxylase (GAD67)

PDB ID 2okj

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