5htk | pdb_00005htk

Human Heart 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase (PFKFB2)

spinqualitylabelsall models 5htk, resolution 2.01Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5htk is a 2 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 2.01Å Ligands: ATP, EDO, F6P, FLC, GOL, MES, MG, NEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function F262_HUMAN Synthesis and degradation of fructose 2,6-bisphosphate. Publication Abstract from PubMed The heart-specific isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) is an important regulator of glycolytic flux in cardiac cells. Here, we present the crystal structures of two PFKFB2 orthologues, human and bovine, at resolutions of 2.0 and 1.8 A, respectively. Citrate, a TCA cycle intermediate and well-known inhibitor of PFKFB2, co-crystallized in the 2-kinase domains of both orthologues, occupying the fructose-6-phosphate binding-site and extending into the gamma-phosphate binding pocket of ATP. This steric and electrostatic occlusion of the gamma-phosphate site by citrate proved highly consequential to the binding of co-complexed ATP analogues. The bovine structure, which co-crystallized with ADP, closely resembled the overall structure of other PFKFB isoforms, with ADP mimicking the catalytic binding mode of ATP. The human structure, on the other hand, co-complexed with AMPPNP, which, unlike ADP, contains a gamma-phosphate. The presence of this gamma-phosphate made adoption of the catalytic ATP binding mode impossible for AMPPNP, forcing the analogue to bind atypically with concomitant conformational changes to the ATP binding-pocket. Inhibition kinetics were used to validate the structural observations, confirming citrate's inhibition mechanism as competitive for F6P and noncompetitive for ATP. Together, these structural and kinetic data establish a molecular basis for citrate's negative feed-back loop of the glycolytic pathway via PFKFB2. Proteins 2016. (c) 2016 Wiley Periodicals, Inc. Crystal structure of heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) and the inhibitory influence of citrate on substrate binding.,Crochet RB, Kim JD, Lee H, Yim YS, Kim SG, Neau D, Lee YH Proteins. 2016 Nov 1. doi: 10.1002/prot.25204. PMID:27802586 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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