1t5a: Difference between revisions
New page: left|200px<br /> <applet load="1t5a" size="450" color="white" frame="true" align="right" spinBox="true" caption="1t5a, resolution 2.8Å" /> '''Human Pyruvate Kinas... |
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[[Image:1t5a.gif|left|200px]]<br /> | [[Image:1t5a.gif|left|200px]]<br /><applet load="1t5a" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1t5a, resolution 2.8Å" /> | caption="1t5a, resolution 2.8Å" /> | ||
'''Human Pyruvate Kinase M2'''<br /> | '''Human Pyruvate Kinase M2'''<br /> | ||
==Overview== | ==Overview== | ||
Four isozymes of pyruvate kinase are differentially expressed in human | 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. | ||
==Disease== | |||
Known disease associated with this structure: Kallmann syndrome 4 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607002 607002]] | |||
==About this Structure== | ==About this Structure== | ||
1T5A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FBP, OXL, PO4, MG, K and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Pyruvate_kinase Pyruvate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.40 2.7.1.40] Full crystallographic information is available from [http:// | 1T5A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=FBP:'>FBP</scene>, <scene name='pdbligand=OXL:'>OXL</scene>, <scene name='pdbligand=PO4:'>PO4</scene>, <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=K:'>K</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Pyruvate_kinase Pyruvate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.40 2.7.1.40] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T5A OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Pyruvate kinase]] | [[Category: Pyruvate kinase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Dombrauckas, J | [[Category: Dombrauckas, J D.]] | ||
[[Category: Mesecar, A | [[Category: Mesecar, A D.]] | ||
[[Category: Santarsiero, B | [[Category: Santarsiero, B D.]] | ||
[[Category: FBP]] | [[Category: FBP]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
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[[Category: beta sheets]] | [[Category: beta sheets]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:10:00 2008'' | ||
Revision as of 16:10, 21 February 2008
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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.
DiseaseDisease
Known disease associated with this structure: Kallmann syndrome 4 OMIM:[607002]
About this StructureAbout this Structure
1T5A is a Single protein structure of sequence from Homo sapiens with , , , , and 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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