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2fhi

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Revision as of 08:59, 14 June 2018

SUBSTRATE ANALOG (IB2) COMPLEX WITH THE HIS 96 ASN SUBSTITUTION OF THE FRAGILE HISTIDINE TRIAD PROTEIN, FHIT

Structural highlights

2fhi is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	FHIT (HUMAN)
Activity:	Bis(5'-adenosyl)-triphosphatase, with EC number 3.6.1.29
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[FHIT_HUMAN] Note=A chromosomal aberration involving FHIT has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation t(3;8)(p14.2;q24.1) with RNF139. Although the 3p14.2 breakpoint has been shown to interrupt FHIT in its 5-prime non-coding region, it is unlikely that FHIT is causally related to renal or other malignancies.^[1] Note=Associated with digestive tract cancers. Numerous tumor types are found to have aberrant forms of FHIT protein due to deletions in a coding region of chromosome 3p14.2 including the fragile site locus FRA3B.^[2]

Function

[FHIT_HUMAN] Cleaves A-5'-PPP-5'A to yield AMP and ADP. Possible tumor suppressor for specific tissues.^[3]

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

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pekarsky Y, Garrison PN, Palamarchuk A, Zanesi N, Aqeilan RI, Huebner K, Barnes LD, Croce CM. Fhit is a physiological target of the protein kinase Src. Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3775-9. Epub 2004 Mar 8. PMID:15007172 doi:10.1073/pnas.0400481101
↑ Pekarsky Y, Garrison PN, Palamarchuk A, Zanesi N, Aqeilan RI, Huebner K, Barnes LD, Croce CM. Fhit is a physiological target of the protein kinase Src. Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3775-9. Epub 2004 Mar 8. PMID:15007172 doi:10.1073/pnas.0400481101
↑ Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K. Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase. Biochemistry. 1996 Sep 10;35(36):11529-35. PMID:8794732 doi:10.1021/bi961415t
↑ 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

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2fhi"

@@ Line 1: / Line 1: @@
 ==SUBSTRATE ANALOG (IB2) COMPLEX WITH THE HIS 96 ASN SUBSTITUTION OF THE FRAGILE HISTIDINE TRIAD PROTEIN, FHIT==
 <StructureSection load='2fhi' size='340' side='right' caption='[[2fhi]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FHIT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2fhi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fhi OCA], [http://pdbe.org/2fhi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2fhi RCSB], [http://www.ebi.ac.uk/pdbsum/2fhi PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2fhi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fhi OCA], [http://pdbe.org/2fhi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2fhi RCSB], [http://www.ebi.ac.uk/pdbsum/2fhi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2fhi ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 16: / Line 17: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fh/2fhi_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fh/2fhi_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>

2fhi

From Proteopedia

Revision as of 08:59, 14 June 2018

SUBSTRATE ANALOG (IB2) COMPLEX WITH THE HIS 96 ASN SUBSTITUTION OF THE FRAGILE HISTIDINE TRIAD PROTEIN, FHIT

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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