{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T15:25:32Z","timestamp":1789745132599,"version":"4.0.1"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,6,11]]},"abstract":"<jats:p>\n                    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 \u03b1-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, (\n                    <jats:italic>S<\/jats:italic>\n                    )-\u03b1-chloro-phenylpropionic acid [(\n                    <jats:italic>S<\/jats:italic>\n                    )-CPP]. Crystal structures of the BDK-(\n                    <jats:italic>S<\/jats:italic>\n                    )-CPP complex show that (\n                    <jats:italic>S<\/jats:italic>\n                    )-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 (\n                    <jats:italic>S<\/jats:italic>\n                    )-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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1303220110","type":"journal-article","created":{"date-parts":[[2013,5,29]],"date-time":"2013-05-29T01:46:29Z","timestamp":1369791989000},"page":"9728-9733","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":71,"title":["Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain \u03b1-ketoacid dehydrogenase kinase"],"prefix":"10.1073","volume":"110","author":[{"given":"Shih-Chia","family":"Tso","sequence":"first","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangbing","family":"Qi","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Jun","family":"Gui","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacinta L.","family":"Chuang","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine K.","family":"Morlock","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamran","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Laxman","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe M.","family":"Campeau","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan H.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030;"},{"name":"Howard Hughes Medical Institute, Houston, TX 77030; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Hutson","sequence":"additional","affiliation":[{"name":"Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, VA 24061"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin P.","family":"Tu","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelle S.","family":"Williams","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uttam K.","family":"Tambar","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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Annu Rev Nutr 4, 409\u2013454 (1984).","journal-title":"Annu Rev Nutr"},{"key":"e_1_3_4_2_2","first-page":"1971","volume-title":"The Metabolic and Molecular Basis of Inherited Disease","author":"Chuang DT","year":"2001","unstructured":"DT Chuang, VE Shih, Maple syrup urine disease (Branched-chain ketoaciduria). The Metabolic and Molecular Basis of Inherited Disease, eds CR Scriver, et al. (McGraw-Hill, 8th Ed, New York), pp. 1971\u20132006 (2001).","edition":"8"},{"key":"e_1_3_4_3_2","first-page":"1","volume-title":"The Online Metabolic and Molecular Basis of Inherited Disease","author":"Chuang DT","year":"2008","unstructured":"DT Chuang, RM Wynn, VE Shih, Maple syrup urine disease (branched-chain ketoaciduria): An update. The Online Metabolic and Molecular Basis of Inherited Disease, eds CR Scriver, et al. (McGraw Hill, New York), pp. 1\u201342 (2008)."},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.cmet.2009.02.002","article-title":"A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance","volume":"9","author":"Newgard CB","year":"2009","unstructured":"CB Newgard, et al., A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9, 311\u2013326 (2009).","journal-title":"Cell Metab"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.cmet.2012.01.024","article-title":"Interplay between lipids and branched-chain amino acids in development of insulin resistance","volume":"15","author":"Newgard CB","year":"2012","unstructured":"CB Newgard, Interplay between lipids and branched-chain amino acids in development of insulin resistance. 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