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| | {{STRUCTURE_1d8d| PDB=1d8d | SCENE= }} | | {{STRUCTURE_1d8d| PDB=1d8d | SCENE= }} |
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| - | '''CO-CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH A K-RAS4B PEPTIDE SUBSTRATE AND FPP ANALOG AT 2.0A RESOLUTION'''
| + | ===CO-CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH A K-RAS4B PEPTIDE SUBSTRATE AND FPP ANALOG AT 2.0A RESOLUTION=== |
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| - | ==Overview==
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| - | Background: The protein farnesyltransferase (FTase) catalyzes addition of the hydrophobic farnesyl isoprenoid to a cysteine residue fourth from the C terminus of several protein acceptors that are essential for cellular signal transduction such as Ras and Rho. This addition is necessary for the biological function of the modified proteins. The majority of Ras-related human cancers are associated with oncogenic variants of K-RasB, which is the highest affinity natural substrate of FTase. Inhibition of FTase causes regression of Ras-mediated tumors in animal models. Results: We present four ternary complexes of rat FTase co-crystallized with farnesyl diphosphate analogs and K-Ras4B peptide substrates. The Ca(1)a(2)X portion of the peptide substrate binds in an extended conformation in the hydrophobic cavity of FTase and coordinates the active site zinc ion. These complexes offer the first view of the polybasic region of the K-Ras4B peptide substrate, which confers the major enhancement of affinity of this substrate. The polybasic region forms a type I beta turn and binds along the rim of the hydrophobic cavity. Removal of the catalytically essential zinc ion results in a dramatically different peptide conformation in which the Ca(1)a(2)X motif adopts a beta turn. A manganese ion binds to the diphosphate mimic of the farnesyl diphosphate analog. Conclusions: These ternary complexes provide new insight into the molecular basis of peptide substrate specificity, and further define the roles of zinc and magnesium in the prenyltransferase reaction. Zinc is essential for productive Ca(1)a(2)X peptide binding, suggesting that the beta-turn conformation identified in previous nuclear magnetic resonance (NMR) studies reflects a state in which the cysteine is not coordinated to the zinc ion. The structural information presented here should facilitate structure-based design and optimization of inhibitors of Ca(1)a(2)X protein prenyltransferases.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10673434}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10673434 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10673434}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Pftase]] | | [[Category: Pftase]] |
| | [[Category: Ra]] | | [[Category: Ra]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 13:33:46 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 22:39:48 2008'' |
Revision as of 19:39, 30 June 2008
Template:STRUCTURE 1d8d
CO-CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH A K-RAS4B PEPTIDE SUBSTRATE AND FPP ANALOG AT 2.0A RESOLUTION
Template:ABSTRACT PUBMED 10673434
About this Structure
1D8D is a Protein complex structure of sequences from Rattus norvegicus. Full crystallographic information is available from OCA.
Reference
The basis for K-Ras4B binding specificity to protein farnesyltransferase revealed by 2 A resolution ternary complex structures., Long SB, Casey PJ, Beese LS, Structure. 2000 Feb 15;8(2):209-22. PMID:10673434
Page seeded by OCA on Mon Jun 30 22:39:48 2008
