1d8d

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spinqualitylabelsall models 1d8d, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CO-CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH A K-RAS4B PEPTIDE SUBSTRATE AND FPP ANALOG AT 2.0A RESOLUTION

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known diseases associated with this structure: Bladder cancer OMIM:[190070], Breast cancer, somatic OMIM:[190070], Costello syndrome OMIM:[190070], Leukemia, acute myelogenous OMIM:[190070], Lung cancer OMIM:[190070], Noonan syndrome 3 OMIM:[190070], Pancreatic carcinoma, somatic OMIM:[190070], Stomach cancer OMIM:[190070]

About this Structure

1D8D is a Protein complex structure of sequences from Rattus norvegicus with ACT, ZN and FII as ligands. Active as Squalene synthase, with EC number 2.5.1.21 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

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