1jcs

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{{STRUCTURE_1jcs| PDB=1jcs | SCENE= }}
{{STRUCTURE_1jcs| PDB=1jcs | SCENE= }}
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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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===CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH THE PEPTIDE SUBSTRATE TKCVFM AND AN ANALOG OF FARNESYL DIPHOSPHATE===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 11687658 is the PubMed ID number.
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{{ABSTRACT_PUBMED_11687658}}
==About this Structure==
==About this Structure==
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[[Category: Pftase]]
[[Category: Pftase]]
[[Category: Ra]]
[[Category: Ra]]
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Revision as of 17:02, 1 July 2008

Image:1jcs.png

Template:STRUCTURE 1jcs

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

Template:ABSTRACT PUBMED 11687658

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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