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Reference: Bullock, AN, Russo, S, Amos, A et al., (2009). Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor. PloS one, 4 (10), Article: e7112.Citable link to this page:


Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor.

Abstract: BACKGROUND: The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2. PRINCIPAL FINDINGS: Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level). Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases. SIGNIFICANCE: The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

Publication status:Published Funder: Canadian Institutes for Health Research   Funder: Canadian Foundation for Innovation   Funder: Ontario Genomics Institute   Funder: GlaxoSmithKline   Funder: Karolinska Institutet   Funder: Knut and Alice Wallenberg Foundation   Funder: Ontario Innovation Trust   Funder: Ontario Ministry for Research and Innovation   Funder: Merck and Co Inc   Funder: Novartis Research Foundation   Funder: Swedish Agency for Innovation Systems   Funder: Swedish Foundation for Strategic Research   Funder: Wellcome Trust   Funder: Structural Genomics Consortium   Notes:Copyright 2009 Bullock et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Bibliographic Details

Publisher: Public Library of Science

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Journal: PloS onesee more from them

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Issue Date: 2009

pages:Article: e7112Identifiers

Urn: uuid:75641f80-06c0-4e70-925f-48b0614b6a27

Source identifier: 34939

Eissn: 1932-6203


Issn: 1932-6203 Item Description

Type: Journal article;

Language: eng Keywords: Humans Ruthenium Staurosporine Enzyme Inhibitors Crystallography, X-Ray Protein Conformation Protein Structure, Tertiary Drug Design Binding Sites Molecular Structure Proto-Oncogene Proteins c-pim-1 Chemistry, Pharmaceutical Protein Isoforms Structure-Activity Relationship Tiny URL: pubs:34939


Autor: Bullock, AN - institutionUniversity of Oxford Oxford, MSD, Clinical Medicine, Structural Genomics Consortium - - - Russo, S - - -



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