| Structural highlights
9m3r is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.14Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
PDK2_HUMAN Serine/threonine kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Multiple screening approaches were carried out to identify novel chemistry starting for Pyruvate Dehydrogenase Kinases (PDHKs) inhibitors. Through hit triaging efforts and structure-based optimization, two series of ATP competitive inhibitors with single digit nanomolar enzymatic potency for PDHK1/2 and around 10-100-fold selectivity over PDHK4/3 were discovered. Approach of covalent inhibitor was explored to successfully improve the cellular target engagement to single digit micromolar range.
Discovery of ATP competitive PDHK1/2 dual inhibitors.,Xu H, Ding D, Han X, Miao K, Liang C, Yun H, Zhu W, Dey F, Zhao D, Wu Y, Reutlinger M, Yang J, Zhai G, Lin Z, Li C, Wu W, Xu B, Han L, Chen S, Huang X, Casagrande F, Hilbert M, Strebel Q, Wichert M, Westwood P, Schafer R, Roth D, Heer D, Tian X, Ma T, Zhang T, Zhao J, Urich E, Xia G, Lassen K, Shen HC, Zou G Bioorg Med Chem Lett. 2025 Mar 17;122:130190. doi: 10.1016/j.bmcl.2025.130190. PMID:40107630[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM. Diversity of the pyruvate dehydrogenase kinase gene family in humans. J Biol Chem. 1995 Dec 1;270(48):28989-94. PMID:7499431
- ↑ Majer M, Popov KM, Harris RA, Bogardus C, Prochazka M. Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects. Mol Genet Metab. 1998 Oct;65(2):181-6. PMID:9787110 doi:http://dx.doi.org/10.1006/mgme.1998.2748
- ↑ Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007 Jan;11(1):37-51. PMID:17222789 doi:http://dx.doi.org/10.1016/j.ccr.2006.10.020
- ↑ Li J, Kato M, Chuang DT. Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate. J Biol Chem. 2009 Dec 4;284(49):34458-67. doi: 10.1074/jbc.M109.065557. Epub 2009, Oct 15. PMID:19833728 doi:http://dx.doi.org/10.1074/jbc.M109.065557
- ↑ Sun W, Chang SS, Fu Y, Liu Y, Califano JA. Chronic CSE treatment induces the growth of normal oral keratinocytes via PDK2 upregulation, increased glycolysis and HIF1alpha stabilization. PLoS One. 2011 Jan 19;6(1):e16207. doi: 10.1371/journal.pone.0016207. PMID:21283817 doi:http://dx.doi.org/10.1371/journal.pone.0016207
- ↑ Contractor T, Harris CR. p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res. 2012 Jan 15;72(2):560-7. doi: 10.1158/0008-5472.CAN-11-1215. Epub, 2011 Nov 28. PMID:22123926 doi:http://dx.doi.org/10.1158/0008-5472.CAN-11-1215
- ↑ Xu H, Ding D, Han X, Miao K, Liang C, Yun H, Zhu W, Dey F, Zhao D, Wu Y, Reutlinger M, Yang J, Zhai G, Lin Z, Li C, Wu W, Xu B, Han L, Chen S, Huang X, Casagrande F, Hilbert M, Strebel Q, Wichert M, Westwood P, Schäfer R, Roth D, Heer D, Tian X, Ma T, Zhang T, Zhao J, Urich E, Xia G, Lassen K, Shen HC, Zou G. Discovery of ATP competitive PDHK1/2 dual inhibitors. Bioorg Med Chem Lett. 2025 Mar 17;122:130190. PMID:40107630 doi:10.1016/j.bmcl.2025.130190
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