1riw

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spinqualitylabelsall models 1riw, resolution 2.04Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Thrombin in complex with natural product inhibitor Oscillarin

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The first enantiocontrolled total synthesis of the marine natural product, oscillarin is described. The proposed structure and absolute configuration, of oscillarin is thus confirmed, and a previously assigned structure of a, subunit was shown to be incorrect. The X-ray structure of an, oscillarin-thrombin complex was resolved at 2.0 A resolution, which, validated its potent inhibitory activity against the enzyme with an IC(50), = 28 nM. Methodology was developed for the synthesis of enantiopure, octahydroindole-2-carboxylic acids with usable functionality at C-6. The, method consists of the halocarbocyclization of N-acyloxyiminium ions, containing an olefinic tether in the presence of tin tetrachloride or tin, tetrabromide. This N-acyloxyiminium ion aza-Prins carbocyclization proved, to be general for the construction of octahydroindole and, perhydroquinoline 2-carboxylic acids. Mechanistic rationales are based on, an antiperiplanar attack of the terminal alkene on the iminium ion, leading to an incipient secondary carbocation which is trapped by halide, via an equatorial attack. X-ray crystal structures of products corroborate, the expected stereochemistry.

Disease

Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

1RIW is a Protein complex structure of sequences from Homo sapiens with NAG, SO4, NA and OSC as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

The N-acyloxyiminium ion aza-Prins route to octahydroindoles: total synthesis and structural confirmation of the antithrombotic marine natural product oscillarin., Hanessian S, Tremblay M, Petersen JF, J Am Chem Soc. 2004 May 19;126(19):6064-71. PMID:15137772

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