2vgi | pdb_00002vgi

HUMAN ERYTHROCYTE PYRUVATE KINASE: R486W MUTANT

spinqualitylabelsall models 2vgi, resolution 2.87Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2vgi is a 4 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 1lix. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.87Å Ligands: FBP, K, MN, PGA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KPYR_HUMAN Defects in PKLR are the cause of pyruvate kinase hyperactivity (PKHYP) [MIM:102900; also known as high red cell ATP syndrome. This autosomal dominant phenotype is characterized by increase of red blood cell ATP. Defects in PKLR are the cause of pyruvate kinase deficiency of red cells (PKRD) [MIM:266200. A frequent cause of hereditary non-spherocytic hemolytic anemia. Clinically, pyruvate kinase-deficient patients suffer from a highly variable degree of chronic hemolysis, ranging from severe neonatal jaundice and fatal anemia at birth, severe transfusion-dependent chronic hemolysis, moderate hemolysis with exacerbation during infection, to a fully compensated hemolysis without apparent anemia. Function KPYR_HUMAN Plays a key role in glycolysis (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Deficiency of human erythrocyte isozyme (RPK) is, together with glucose-6-phosphate dehydrogenase deficiency, the most common cause of the nonspherocytic hemolytic anemia. To provide a molecular framework to the disease, we have solved the 2.7 A resolution crystal structure of human RPK in complex with fructose 1,6-bisphosphate, the allosteric activator, and phosphoglycolate, a substrate analogue, and we have functionally and structurally characterized eight mutants (G332S, G364D, T384M, D390N, R479H, R486W, R504L, and R532W) found in RPK-deficient patients. The mutations target distinct regions of RPK structure, including domain interfaces and catalytic and allosteric sites. The mutations affect to a different extent thermostability, catalytic efficiency, and regulatory properties. These studies are the first to correlate the clinical symptoms with the molecular properties of the mutant enzymes. Mutations greatly impairing thermostability and/or activity are associated with severe anemia. Some mutant proteins exhibit moderate changes in the kinetic parameters, which are sufficient to cause mild to severe anemia, underlining the crucial role of RPK for erythrocyte metabolism. Prediction of the effects of mutations is difficult because there is no relation between the nature and location of the replaced amino acid and the type of molecular perturbation. Characterization of mutant proteins may serve as a valuable tool to assist with diagnosis and genetic counseling. Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia.,Valentini G, Chiarelli LR, Fortin R, Dolzan M, Galizzi A, Abraham DJ, Wang C, Bianchi P, Zanella A, Mattevi A J Biol Chem. 2002 Jun 28;277(26):23807-14. Epub 2002 Apr 17. PMID:11960989 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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