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2fhi
From Proteopedia
| 2fhi, resolution 2.60Å () | |||||||||
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| Sites: | |||||||||
| Ligands: | |||||||||
| Gene: | FHIT (Homo sapiens) | ||||||||
| Activity: | Bis(5'-adenosyl)-triphosphatase, with EC number 3.6.1.29 | ||||||||
| Domains: | FHIT | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
SUBSTRATE ANALOG (IB2) COMPLEX WITH THE HIS 96 ASN SUBSTITUTION OF THE FRAGILE HISTIDINE TRIAD PROTEIN, FHIT
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.
Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit., Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rosler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C, Proc Natl Acad Sci U S A. 1998 May 12;95(10):5484-9. PMID:9576908
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
2FHI is a 1 chain structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rosler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C. Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit. Proc Natl Acad Sci U S A. 1998 May 12;95(10):5484-9. PMID:9576908
Page seeded by OCA on Mon Feb 16 11:28:17 2009
Categories: Homo sapiens | Barnes, L D. | Blackburn, G M. | Brenner, C. | Croce, C M. | Draganescu, A. | Garrison, P N. | Heubner, K. | Pace, H C. | Robinson, A K. | Rosler, A. | Siprashvili, Z. | Active site substitution | Cancer | Diadenosine triphosphate hydrolase | Histidine triad | Nucleotide-binding protein | Tumor suppressor
