| 词条 | PDK3 | |||||||||||||||||||||||||||||||||||||
| 释义 |
StructureThe structure of the PDK3/L2 complex has been elucidated, and there are several key features. When the L2 domain binds to PDK3, it induces a “cross-tail” conformation in PDK3, thereby stimulating activity. There are three crucial residues, Leu-140, Glu-170, and Glu-179, in the C-terminal domain that are crucial for this interaction.[3] Structural studies have indicated that L2 binding stimulates activity by disrupting the closed conformation, or ATP lid, to remove product inhibition.[4] The PDK3 subunits are in one of two conformations; one subunit exists as an “open” subunit, while the other subunit is “closed”. The open subunit is the configuration most crucial to the putative substrate-binding cleft, as it is where the target peptide can access the active center. The closed subunit blocks this target peptide because of a neighboring unwound alpha helix. Additionally, the ATP-binding loop in one PDK3 subunit adopts an open conformation, implying that the nucleotide loading into the active site is mediated by the inactive "pre-insertion" binding mode. This asymmetric complex represents a physiological state in which binding of a single L2-domain activates one of the PDHK subunits while inactivating another.[5] Thus, the L2-domains likely act not only as the structural anchors but also modulate the catalytic cycle of PDK3. FunctionThe Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four isozymes of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: PDK1, PDK2, PDK3, and PDK4.[6] The PDK3 protein is primarily found in the kidney, brain, and testis.[7] RegulationAs the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors. PDK3, in conjunction with PDK2 and PDK4, are primary targets of peroxisome proliferator-activated receptor delta/beta (PPAR beta/delta), with PDK3 having five elements that respond to these receptors.[8] Model organismsModel organisms have been used in the study of PDK3 function. A conditional knockout mouse line called Pdk3tm2a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[9] Male and female animals underwent a standardized phenotypic screen[10] to determine the effects of deletion.[11][12][13][14] Additional screens performed: - In-depth immunological phenotyping[15]
References1. ^{{cite journal | vauthors = Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM | title = Diversity of the pyruvate dehydrogenase kinase gene family in humans | journal = The Journal of Biological Chemistry | volume = 270 | issue = 48 | pages = 28989–94 | date = Dec 1995 | pmid = 7499431 | doi = 10.1074/jbc.270.48.28989 }} 2. ^1 {{cite web | title = Entrez Gene: PDK3 pyruvate dehydrogenase kinase, isozyme 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5165| accessdate = }} 3. ^{{cite journal | vauthors = Tso SC, Kato M, Chuang JL, Chuang DT | title = Structural determinants for cross-talk between pyruvate dehydrogenase kinase 3 and lipoyl domain 2 of the human pyruvate dehydrogenase complex | journal = The Journal of Biological Chemistry | volume = 281 | issue = 37 | pages = 27197–204 | date = Sep 2006 | pmid = 16849321 | doi = 10.1074/jbc.M604339200 }} 4. ^{{cite journal | vauthors = Kato M, Chuang JL, Tso SC, Wynn RM, Chuang DT | title = Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex | journal = The EMBO Journal | volume = 24 | issue = 10 | pages = 1763–74 | date = May 2005 | pmid = 15861126 | pmc = 1142596 | doi = 10.1038/sj.emboj.7600663 }} 5. ^{{cite journal | vauthors = Devedjiev Y, Steussy CN, Vassylyev DG | title = Crystal structure of an asymmetric complex of pyruvate dehydrogenase kinase 3 with lipoyl domain 2 and its biological implications | journal = Journal of Molecular Biology | volume = 370 | issue = 3 | pages = 407–16 | date = Jul 2007 | pmid = 17532006 | pmc = 1994203 | doi = 10.1016/j.jmb.2007.04.083 }} 6. ^{{cite journal | vauthors = Kolobova E, Tuganova A, Boulatnikov I, Popov KM | title = Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites | journal = The Biochemical Journal | volume = 358 | issue = Pt 1 | pages = 69–77 | date = Aug 2001 | pmid = 11485553 | pmc = 1222033 | doi = 10.1042/0264-6021:3580069 }} 7. ^{{cite journal | vauthors = Sugden MC, Holness MJ | title = Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the prevention of hyperglycaemia | journal = Current Drug Targets. Immune, Endocrine and Metabolic Disorders | volume = 2 | issue = 2 | pages = 151–65 | date = Jul 2002 | pmid = 12476789 | doi = 10.2174/1568005310202020151 }} 8. ^{{cite journal | vauthors = Degenhardt T, Saramäki A, Malinen M, Rieck M, Väisänen S, Huotari A, Herzig KH, Müller R, Carlberg C | title = Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor beta/delta | journal = Journal of Molecular Biology | volume = 372 | issue = 2 | pages = 341–55 | date = Sep 2007 | pmid = 17669420 | doi = 10.1016/j.jmb.2007.06.091 }} 9. ^{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice |author=Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x }} 10. ^1 {{cite web |url=http://www.mousephenotype.org/data/search?q=Pdk3#fq=**&facet=gene |title=International Mouse Phenotyping Consortium}} 11. ^{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = Jun 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }} 12. ^{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = Jun 2011 | pmid = 21677718 | doi = 10.1038/474262a }} 13. ^{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = Jan 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }} 14. ^{{cite journal | vauthors = White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–64 | date = Jul 2013 | pmid = 23870131 | pmc = 3717207 | doi = 10.1016/j.cell.2013.06.022 }} 15. ^1 {{cite web |url= http://www.immunophenotyping.org/data/search?keys=Pdk3&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}} Further reading{{refbegin|33em}}
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