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| | <StructureSection load='3tz2' size='340' side='right'caption='[[3tz2]], [[Resolution|resolution]] 2.85Å' scene=''> | | <StructureSection load='3tz2' size='340' side='right'caption='[[3tz2]], [[Resolution|resolution]] 2.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3tz2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TZ2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TZ2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3tz2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TZ2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TZ2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLT:4-PHENYL-BUTANOIC+ACID'>CLT</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.85Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3tz0|3tz0]], [[3tz4|3tz4]], [[3tz5|3tz5]], [[4h85|4h85]], [[4dzy|4dzy]], [[4h7q|4h7q]], [[4h81|4h81]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLT:4-PHENYL-BUTANOIC+ACID'>CLT</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Bckdk ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr> | + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/[3-methyl-2-oxobutanoate_dehydrogenase_(acetyl-transferring)]_kinase [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.4 2.7.11.4] </span></td></tr>
| + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3tz2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tz2 OCA], [https://pdbe.org/3tz2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tz2 RCSB], [https://www.ebi.ac.uk/pdbsum/3tz2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tz2 ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3tz2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tz2 OCA], [https://pdbe.org/3tz2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tz2 RCSB], [https://www.ebi.ac.uk/pdbsum/3tz2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tz2 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/BCKD_RAT BCKD_RAT]] Catalyzes the phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, the key regulatory enzyme of the valine, leucine and isoleucine catabolic pathways. Key enzyme that regulate the activity state of the BCKD complex.
| + | [https://www.uniprot.org/uniprot/BCKD_RAT BCKD_RAT] Catalyzes the phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, the key regulatory enzyme of the valine, leucine and isoleucine catabolic pathways. Key enzyme that regulate the activity state of the BCKD complex. |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are elevated in maple syrup urine disease, heart failure, obesity, and type 2 diabetes. BCAA homeostasis is controlled by the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC), which is negatively regulated by the specific BCKD kinase (BDK). Here, we used structure-based design to develop a BDK inhibitor, (S)-alpha-chloro-phenylpropionic acid [(S)-CPP]. Crystal structures of the BDK-(S)-CPP complex show that (S)-CPP binds to a unique allosteric site in the N-terminal domain, triggering helix movements in BDK. These conformational changes are communicated to the lipoyl-binding pocket, which nullifies BDK activity by blocking its binding to the BCKDC core. Administration of (S)-CPP to mice leads to the full activation and dephosphorylation of BCKDC with significant reduction in plasma BCAA concentrations. The results buttress the concept of targeting mitochondrial BDK as a pharmacological approach to mitigate BCAA accumulation in metabolic diseases and heart failure.
| + | |
| - | | + | |
| - | Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain alpha-ketoacid dehydrogenase kinase.,Tso SC, Qi X, Gui WJ, Chuang JL, Morlock LK, Wallace AL, Ahmed K, Laxman S, Campeau PM, Lee BH, Hutson SM, Tu BP, Williams NS, Tambar UK, Wynn RM, Chuang DT Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9728-33. doi:, 10.1073/pnas.1303220110. Epub 2013 May 28. PMID:23716694<ref>PMID:23716694</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 3tz2" style="background-color:#fffaf0;"></div>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chuang, D T]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Chuang, J L]] | + | [[Category: Chuang DT]] |
| - | [[Category: Gui, W J]] | + | [[Category: Chuang JL]] |
| - | [[Category: Li, J]] | + | [[Category: Gui WJ]] |
| - | [[Category: Tso, S C]] | + | [[Category: Li J]] |
| - | [[Category: Wynn, R M]] | + | [[Category: Tso SC]] |
| - | [[Category: Allosteric kinase inhibitor]] | + | [[Category: Wynn RM]] |
| - | [[Category: Bergerat nucleotide-binding fold]]
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| - | [[Category: Branched-chain alpha-ketoacid]]
| + | |
| - | [[Category: Branched-chain amino acid]]
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| - | [[Category: Diabetes and obesity]]
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| - | [[Category: Ghkl protein kinase]]
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| - | [[Category: Maple syrup urine disease]]
| + | |
| - | [[Category: Protein kinase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
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