2fhi: Difference between revisions
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==Overview== | ==Overview== | ||
Alterations in the FHIT gene at 3p14.2 occur as early and frequent events, in the development of several common human cancers. The ability of human, Fhit-negative cells to form tumors in nude mice is suppressed by stable, reexpression of Fhit protein. Fhit protein is a diadenosine, P1,P3-triphosphate (ApppA) hydrolase whose fungal and animal homologs form, a branch of the histidine triad (HIT) superfamily of nucleotide-binding, proteins. Because the His-96 --> Asn substitution of Fhit, which retards, ApppA hydrolase activity by seven orders of magnitude, did not block, tumor-suppressor activity in vivo, we determined whether this mutation, affected ApppA binding or particular steps in the ApppA catalytic cycle., Evidence is presented that His-96 --> Asn protein binds ApppA well and, ... | Alterations in the FHIT gene at 3p14.2 occur as early and frequent events, in the development of several common human cancers. The ability of human, Fhit-negative cells to form tumors in nude mice is suppressed by stable, reexpression of Fhit protein. Fhit protein is a diadenosine, P1,P3-triphosphate (ApppA) hydrolase whose fungal and animal homologs form, a branch of the histidine triad (HIT) superfamily of nucleotide-binding, proteins. Because the His-96 --> Asn substitution of Fhit, which retards, ApppA hydrolase activity by seven orders of magnitude, did not block, tumor-suppressor activity in vivo, we determined whether this mutation, affected ApppA binding or particular steps in the ApppA catalytic cycle., Evidence is presented that His-96 --> Asn protein binds ApppA well and, forms an enzyme-AMP intermediate extremely poorly, suggesting that, Fhit-substrate complexes are the likely signaling form of the enzyme. The, cocrystal structure of Fhit bound to Ado-p-CH2-p-ps-Ado (IB2), a, nonhydrolyzable ApppA analog, was refined to 3.1 A, and the structure of, His-96 --> Asn Fhit with IB2 was refined to 2.6 A, revealing that two, ApppA molecules bind per Fhit dimer; identifying two additional, adenosine-binding sites on the dimer surface; and illustrating that His-98, is positioned to donate a hydrogen bond to the scissile bridging oxygen of, ApppA substrates. The form of Fhit bound to two ApppA substrates would, present to the cell a dramatically phosphorylated surface, prominently, displaying six phosphate groups and two adenosine moieties in place of a, deep cavity lined with histidines, arginines, and glutamines. | ||
==About this Structure== | ==About this Structure== | ||
2FHI is a | 2FHI 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 IB2 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Bis(5'-adenosyl)-triphosphatase Bis(5'-adenosyl)-triphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.29 3.6.1.29] Structure known Active Site: HIT. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2FHI OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: tumor suppressor]] | [[Category: tumor suppressor]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 14:22:59 2007'' | ||
