1jcq
From Proteopedia
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| - | [[Image:1jcq.gif|left|200px]] | + | [[Image:1jcq.gif|left|200px]] |
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| - | '''CRYSTAL STRUCTURE OF HUMAN PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH FARNESYL DIPHOSPHATE AND THE PEPTIDOMIMETIC INHIBITOR L-739,750''' | + | {{Structure |
| + | |PDB= 1jcq |SIZE=350|CAPTION= <scene name='initialview01'>1jcq</scene>, resolution 2.30Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=SUC:SUCROSE'>SUC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=FPP:FARNESYL+DIPHOSPHATE'>FPP</scene>, <scene name='pdbligand=739:2(S)-{2(S)-[2(R)-AMINO-3-MERCAPTO]PROPYLAMINO-3(S)-METHYL}PENTYLOXY-3-PHENYLPROPIONYLMETHIONINE+SULFONE'>739</scene> and <scene name='pdbligand=ACY:ACETIC ACID'>ACY</scene> | ||
| + | |ACTIVITY= | ||
| + | |GENE= | ||
| + | }} | ||
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| + | '''CRYSTAL STRUCTURE OF HUMAN PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH FARNESYL DIPHOSPHATE AND THE PEPTIDOMIMETIC INHIBITOR L-739,750''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1JCQ is a [ | + | 1JCQ is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JCQ OCA]. |
==Reference== | ==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:[http:// | + | 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: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
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[[Category: pft]] | [[Category: pft]] | ||
[[Category: pftase]] | [[Category: pftase]] | ||
| - | [[Category: | + | [[Category: ra]] |
[[Category: tumor regression]] | [[Category: tumor regression]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:01:39 2008'' |
Revision as of 10:01, 20 March 2008
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| , resolution 2.30Å | |||||||
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| Ligands: | , , , and | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF HUMAN PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH FARNESYL DIPHOSPHATE AND THE PEPTIDOMIMETIC INHIBITOR L-739,750
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
1JCQ is a Protein complex structure of sequences from Homo sapiens. 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
Page seeded by OCA on Thu Mar 20 12:01:39 2008
Categories: Homo sapiens | Protein complex | Beese, L S. | Casey, P J. | Long, S B. | 739 | ACY | FPP | SUC | ZN | 750 | Caax | Cancer | Farnesyl protein transferase | Farnesyl transferase | Farnesyltransferase | Fpt | Ft | Ftase | Inhibitor | L-739 | Peptidomimetic | Pft | Pftase | Ra | Tumor regression
