8F5S

human branched chain ketoacid dehydrogenase kinase in complex with inhibitors

Summary for 8F5S

• Entry DOI: 10.2210/pdb8f5s/pdb
• Related: 8F5F
• Descriptor: [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (7 entities in total)
• Functional Keywords: branched chain ketoacid dehydrogenase kinase, inhibitor, signaling protein, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 90516.40

Authors

Liu, S.,Roth Flach, R.,Bollinger, E.,Filipski, K. (deposition date: 2022-11-15, release date: 2023-07-05, Last modification date: 2023-08-23)

Primary citation

Roth Flach, R.J.,Bollinger, E.,Reyes, A.R.,Laforest, B.,Kormos, B.L.,Liu, S.,Reese, M.R.,Martinez Alsina, L.A.,Buzon, L.,Zhang, Y.,Bechle, B.,Rosado, A.,Sahasrabudhe, P.V.,Knafels, J.,Bhattacharya, S.K.,Omoto, K.,Stansfield, J.C.,Hurley, L.D.,Song, L.,Luo, L.,Breitkopf, S.B.,Monetti, M.,Cunio, T.,Tierney, B.,Geoly, F.J.,Delmore, J.,Siddall, C.P.,Xue, L.,Yip, K.N.,Kalgutkar, A.S.,Miller, R.A.,Zhang, B.B.,Filipski, K.J.
Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels.
Nat Commun, 14:4812-4812, 2023

PubMed Abstract: Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led to identification of thiophene PF-07208254, which improved cardiometabolic endpoints in mice. Structure-activity relationship studies led to identification of a thiazole series of BDK inhibitors; however, these inhibitors did not improve metabolism in mice upon chronic administration. While the thiophenes demonstrated sustained branched chain ketoacid (BCKA) lowering and reduced BDK protein levels, the thiazoles increased BCKAs and BDK protein levels. Thiazoles increased BDK proximity to BCKDH-E2, whereas thiophenes reduced BDK proximity to BCKDH-E2, which may promote BDK degradation. Thus, we describe two BDK inhibitor series that possess differing attributes regarding BDK degradation or stabilization and provide a mechanistic understanding of the desirable features of an effective BDK inhibitor.

PubMed: 37558654
DOI: 10.1038/s41467-023-40536-y

Experimental method

X-RAY DIFFRACTION (2.793 Å)