5kpt
PANK3-AMPPNP complex
Structural highlights
FunctionPANK3_HUMAN Plays a role in the physiological regulation of the intracellular CoA concentration (By similarity). Publication Abstract from PubMedPantothenate kinase is the master regulator of CoA biosynthesis, and is feedback inhibited by acetyl-CoA. Comparison of the human PANK3-acetyl-CoA complex to the structures of PANK3 in four catalytically relevant complexes, AMPPNP-Mg2+, AMPPNP-Mg2+-pantothenate, ADP-Mg2+-phosphopantothenate, and AMPPN-Mg2+ revealed a large conformational change in the dimeric enzyme. The amino-terminal nucleotide binding domain rotates to close the active site, and this allows the P-loop to engage ATP and facilitates required substrate/product interactions at the active site. Biochemical analyses showed that the transition between the inactive and active conformations, as assessed by the binding of either ATP-Mg2+ or acyl-CoA to PANK3 is highly cooperative indicating that both protomers move in concert. PANK3(G19V) cannot bind ATP, and biochemical analyses of an engineered PANK3/PANK3(G19V) heterodimer confirmed that the two active sites are functionally coupled. The communication between the two protomers is mediated by an alpha-helix that interacts with the ATP binding site at its amino terminus and with the substrate/inhibitor binding site of the opposite protomer at its carboxy terminus. The two alpha-helices within the dimer together with the bound ligands create a ring that stabilizes the assembly in either the active, closed conformation or the inactive, open conformation. Thus, both active sites of the dimeric mammalian pantothenate kinases coordinately switch between the on and off states in response to intracellular concentrations of ATP and its key negative regulators, acetyl(acyl)-CoA. Allosteric Regulation of Mammalian Pantothenate Kinase.,Subramanian C, Yun MK, Yao J, Sharma LK, Lee RE, White SW, Jackowski S, Rock CO J Biol Chem. 2016 Aug 23. pii: jbc.M116.748061. PMID:27555321[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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