1gjv
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Mitochondrial protein kinases (mPKs) are molecular switches that | + | Mitochondrial protein kinases (mPKs) are molecular switches that down-regulate the oxidation of branched-chain alpha-ketoacids and pyruvate. Elevated levels of these metabolites are implicated in disease states such as insulin-resistant Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. We report a three-dimensional structure of a member of the mPK family, rat branched-chain alpha-ketoacid dehydrogenase kinase (BCK). BCK features a characteristic nucleotide-binding domain and a four-helix bundle domain. These two domains are reminiscent of modules found in protein histidine kinases (PHKs), which are involved in two-component signal transduction systems. Unlike PHKs, BCK dimerizes through direct interaction of two opposing nucleotide-binding domains. Nucleotide binding to BCK is uniquely mediated by both potassium and magnesium. Binding of ATP induces disorder-order transitions in a loop region at the nucleotide-binding site. These structural changes lead to the formation of a quadruple aromatic stack in the interface between the nucleotide-binding domain and the four-helix bundle domain, where they induce a movement of the top portion of two helices. Phosphotransfer induces further ordering of the loop region, effectively trapping the reaction product ADP, which explains product inhibition in mPKs. The BCK structure is a prototype for all mPKs and will provide a framework for structure-assisted inhibitor design for this family of kinases. |
==About this Structure== | ==About this Structure== | ||
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[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Transferred entry: 2 | + | [[Category: Transferred entry: 2 7.11 4]] |
| - | [[Category: Chuang, D | + | [[Category: Chuang, D T.]] |
| - | [[Category: Chuang, J | + | [[Category: Chuang, J L.]] |
[[Category: Machius, M.]] | [[Category: Machius, M.]] | ||
| - | [[Category: Tomchick, D | + | [[Category: Tomchick, D R.]] |
| - | [[Category: Wynn, R | + | [[Category: Wynn, R M.]] |
[[Category: CL]] | [[Category: CL]] | ||
[[Category: K]] | [[Category: K]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:50:55 2008'' |
Revision as of 10:50, 21 February 2008
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BRANCHED-CHAIN ALPHA-KETOACID DEHYDROGENASE KINASE (BCK) COMPLXED WITH ATP-GAMMA-S
Overview
Mitochondrial protein kinases (mPKs) are molecular switches that down-regulate the oxidation of branched-chain alpha-ketoacids and pyruvate. Elevated levels of these metabolites are implicated in disease states such as insulin-resistant Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. We report a three-dimensional structure of a member of the mPK family, rat branched-chain alpha-ketoacid dehydrogenase kinase (BCK). BCK features a characteristic nucleotide-binding domain and a four-helix bundle domain. These two domains are reminiscent of modules found in protein histidine kinases (PHKs), which are involved in two-component signal transduction systems. Unlike PHKs, BCK dimerizes through direct interaction of two opposing nucleotide-binding domains. Nucleotide binding to BCK is uniquely mediated by both potassium and magnesium. Binding of ATP induces disorder-order transitions in a loop region at the nucleotide-binding site. These structural changes lead to the formation of a quadruple aromatic stack in the interface between the nucleotide-binding domain and the four-helix bundle domain, where they induce a movement of the top portion of two helices. Phosphotransfer induces further ordering of the loop region, effectively trapping the reaction product ADP, which explains product inhibition in mPKs. The BCK structure is a prototype for all mPKs and will provide a framework for structure-assisted inhibitor design for this family of kinases.
About this Structure
1GJV is a Single protein structure of sequence from Rattus norvegicus with , , and as ligands. Active as Transferred entry: 2.7.11.4, with EC number 2.7.1.115 Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase., Machius M, Chuang JL, Wynn RM, Tomchick DR, Chuang DT, Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11218-23. Epub 2001 Sep 18. PMID:11562470
Page seeded by OCA on Thu Feb 21 12:50:55 2008
