1t5a
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Human Pyruvate Kinase M2
OverviewOverview
Four isozymes of pyruvate kinase are differentially expressed in human, tissue. Human pyruvate kinase isozyme M2 (hPKM2) is expressed in early, fetal tissues and is progressively replaced by the other three isozymes, M1, R, and L, immediately after birth. In most cancer cells, hPKM2 is once, again expressed to promote tumor cell proliferation. Because of its almost, ubiquitous presence in cancer cells, hPKM2 has been designated as tumor, specific PK-M2, and its presence in human plasma is currently being used, as a molecular marker for the diagnosis of various cancers. The X-ray, structure of human hPKM2 complexed with Mg(2+), K(+), the inhibitor, oxalate, and the allosteric activator fructose 1,6-bisphosphate (FBP) has, been determined to a resolution of 2.82 A. The active site of hPKM2 is in, a partially closed conformation most likely resulting from a, ligand-induced domain closure promoted by the binding of FBP. In all four, subunits of the enzyme tetramer, a conserved water molecule is observed on, the 2-si face of the prospective enolate and supports the hypothesis that, a proton-relay system is acting as the proton donor of the reaction (1)., Significant structural differences among the human M2, rabbit muscle M1, and the human R isozymes are observed, especially in the orientation of, the FBP-activating loop, which is in a closed conformation when FBP is, bound. The structural differences observed between the PK isozymes could, potentially be exploited as unique structural templates for the design of, allosteric drugs against the disease states associated with the various PK, isozymes, especially cancer and nonspherocytic hemolytic anemia.
About this StructureAbout this Structure
1T5A is a Single protein structure of sequence from Homo sapiens with FBP, OXL, PO4, MG, K and GOL as ligands. Active as Pyruvate kinase, with EC number 2.7.1.40 Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis., Dombrauckas JD, Santarsiero BD, Mesecar AD, Biochemistry. 2005 Jul 12;44(27):9417-29. PMID:15996096
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