1jcs

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[[Image:1jcs.gif|left|200px]]<br /><applet load="1jcs" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1jcs.gif|left|200px]]
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caption="1jcs, resolution 2.20&Aring;" />
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'''CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH THE PEPTIDE SUBSTRATE TKCVFM AND AN ANALOG OF FARNESYL DIPHOSPHATE'''<br />
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{{Structure
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|PDB= 1jcs |SIZE=350|CAPTION= <scene name='initialview01'>1jcs</scene>, resolution 2.20&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=FII:[(3,7,11-TRIMETHYL-DODECA-2,6,10-TRIENYLOXYCARBAMOYL)-METHYL]-PHOSPHONIC+ACID'>FII</scene> and <scene name='pdbligand=ACY:ACETIC ACID'>ACY</scene>
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|ACTIVITY=
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|GENE=
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}}
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'''CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH THE PEPTIDE SUBSTRATE TKCVFM AND AN ANALOG OF FARNESYL DIPHOSPHATE'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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1JCS is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=FII:'>FII</scene> and <scene name='pdbligand=ACY:'>ACY</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JCS OCA].
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1JCS is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JCS OCA].
==Reference==
==Reference==
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The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics., Long SB, Hancock PJ, Kral AM, Hellinga HW, Beese LS, Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):12948-53. Epub 2001 Oct 30. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11687658 11687658]
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The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics., Long SB, Hancock PJ, Kral AM, Hellinga HW, Beese LS, Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):12948-53. Epub 2001 Oct 30. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11687658 11687658]
[[Category: Protein complex]]
[[Category: Protein complex]]
[[Category: Rattus norvegicus]]
[[Category: Rattus norvegicus]]
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[[Category: pft]]
[[Category: pft]]
[[Category: pftase]]
[[Category: pftase]]
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[[Category: ras]]
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[[Category: ra]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:21:10 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:01:41 2008''

Revision as of 10:01, 20 March 2008


PDB ID 1jcs

Drag the structure with the mouse to rotate
, resolution 2.20Å
Ligands: , and
Coordinates: save as pdb, mmCIF, xml



CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH THE PEPTIDE SUBSTRATE TKCVFM AND AN ANALOG OF FARNESYL DIPHOSPHATE


Overview

Protein farnesyltransferase (FTase) catalyzes the attachment of a farnesyl lipid group to the cysteine residue located in the C-terminal tetrapeptide of many essential signal transduction proteins, including members of the Ras superfamily. Farnesylation is essential both for normal functioning of these proteins, and for the transforming activity of oncogenic mutants. Consequently FTase is an important target for anti-cancer therapeutics. Several FTase inhibitors are currently undergoing clinical trials for cancer treatment. Here, we present the crystal structure of human FTase, as well as ternary complexes with the TKCVFM hexapeptide substrate, CVFM non-substrate tetrapeptide, and L-739,750 peptidomimetic with either farnesyl diphosphate (FPP), or a nonreactive analogue. These structures reveal the structural mechanism of FTase inhibition. Some CaaX tetrapeptide inhibitors are not farnesylated, and are more effective inhibitors than farnesylated CaaX tetrapeptides. CVFM and L-739,750 are not farnesylated, because these inhibitors bind in a conformation that is distinct from the TKCVFM hexapeptide substrate. This non-substrate binding mode is stabilized by an ion pair between the peptide N terminus and the alpha-phosphate of the FPP substrate. Conformational mapping calculations reveal the basis for the sequence specificity in the third position of the CaaX motif that determines whether a tetrapeptide is a substrate or non-substrate. The presence of beta-branched amino acids in this position prevents formation of the non-substrate conformation; all other aliphatic amino acids in this position are predicted to form the non-substrate conformation, provided their N terminus is available to bind to the FPP alpha-phosphate. These results may facilitate further development of FTase inhibitors.

About this Structure

1JCS is a Protein complex structure of sequences from Rattus norvegicus. Full crystallographic information is available from OCA.

Reference

The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics., Long SB, Hancock PJ, Kral AM, Hellinga HW, Beese LS, Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):12948-53. Epub 2001 Oct 30. PMID:11687658

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