2a1h: Difference between revisions
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==X-ray crystal structure of human mitochondrial branched chain aminotransferase (BCATm) complexed with gabapentin== | ==X-ray crystal structure of human mitochondrial branched chain aminotransferase (BCATm) complexed with gabapentin== | ||
<StructureSection load='2a1h' size='340' side='right' caption='[[2a1h]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='2a1h' size='340' side='right'caption='[[2a1h]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2a1h]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[2a1h]] 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=2A1H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2A1H FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=GBN:[1-(AMINOMETHYL)CYCLOHEXYL]ACETIC+ACID'>GBN</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr> | |||
<tr id=' | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2a1h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a1h OCA], [https://pdbe.org/2a1h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2a1h RCSB], [https://www.ebi.ac.uk/pdbsum/2a1h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2a1h ProSAT]</span></td></tr> | ||
< | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/BCAT2_HUMAN BCAT2_HUMAN] Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine. May also function as a transporter of branched chain alpha-keto acids. | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a1/2a1h_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a1/2a1h_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
| Line 35: | Line 33: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Conway | [[Category: Conway M]] | ||
[[Category: Goto | [[Category: Goto M]] | ||
[[Category: Hirotsu | [[Category: Hirotsu K]] | ||
[[Category: Hutson | [[Category: Hutson SM]] | ||
[[Category: Islam | [[Category: Islam MM]] | ||
[[Category: Miyahara | [[Category: Miyahara I]] | ||
[[Category: Yennawar | [[Category: Yennawar N]] | ||
Latest revision as of 11:14, 15 May 2024
X-ray crystal structure of human mitochondrial branched chain aminotransferase (BCATm) complexed with gabapentinX-ray crystal structure of human mitochondrial branched chain aminotransferase (BCATm) complexed with gabapentin
Structural highlights
FunctionBCAT2_HUMAN Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine. May also function as a transporter of branched chain alpha-keto acids. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThis study presents the first three-dimensional structures of human cytosolic branched-chain aminotransferase (hBCATc) isozyme complexed with the neuroactive drug gabapentin, the hBCATc Michaelis complex with the substrate analog, 4-methylvalerate, and the mitochondrial isozyme (hBCATm) complexed with gabapentin. The branched-chain aminotransferases (BCAT) reversibly catalyze transamination of the essential branched-chain amino acids (leucine, isoleucine, valine) to alpha-ketoglutarate to form the respective branched-chain alpha-keto acids and glutamate. The cytosolic isozyme is the predominant BCAT found in the nervous system, and only hBCATc is inhibited by gabapentin. Pre-steady state kinetics show that 1.3 mm gabapentin can completely inhibit the binding of leucine to reduced hBCATc, whereas 65.4 mm gabapentin is required to inhibit leucine binding to hBCATm. Structural analysis shows that the bulky gabapentin is enclosed in the active-site cavity by the shift of a flexible loop that enlarges the active-site cavity. The specificity of gabapentin for the cytosolic isozyme is ascribed at least in part to the location of the interdomain loop and the relative orientation between the small and large domain which is different from these relationships in the mitochondrial isozyme. Both isozymes contain a CXXC center and form a disulfide bond under oxidizing conditions. The structure of reduced hBCATc was obtained by soaking the oxidized hBCATc crystals with dithiothreitol. The close similarity in active-site structures between cytosolic enzyme complexes in the oxidized and reduced states is consistent with the small effect of oxidation on pre-steady state kinetics of the hBCATc first half-reaction. However, these kinetic data do not explain the inactivation of hBCATm by oxidation of the CXXC center. The structural data suggest that there is a larger effect of oxidation on the interdomain loop and residues surrounding the CXXC center in hBCATm than in hBCATc. Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin.,Goto M, Miyahara I, Hirotsu K, Conway M, Yennawar N, Islam MM, Hutson SM J Biol Chem. 2005 Nov 4;280(44):37246-56. Epub 2005 Sep 1. PMID:16141215[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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