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Insight into Functional Membrane Proteins by Solution NMR: The Human Bcl-2 Protein - A Promising Cancer Drug Target
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-0903-6662
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2021 (English)In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 26, no 5, article id 1467Article in journal (Refereed) Published
Abstract [en]

Evasion from programmed cell death (apoptosis) is the main hallmark of cancer and a major cause of resistance to therapy. Many tumors simply ensure survival by over-expressing the cell-protecting (anti-apoptotic) Bcl-2 membrane protein involved in apoptotic regulation. However, the molecular mechanism by which Bcl-2 protein in its mitochondrial outer membrane location protects cells remains elusive due to the absence of structural insight; and current strategies to therapeutically interfere with these Bcl-2 sensitive cancers are limited. Here, we present an NMR-based approach to enable structural insight into Bcl-2 function; an approach also ideal as a fragment-based drug discovery platform for further identification and development of promising molecular Bcl-2 inhibitors. By using solution NMR spectroscopy on fully functional intact human Bcl-2 protein in a membrane-mimicking micellar environment, and constructs with specific functions remaining, we present a strategy for structure determination and specific drug screening of functional subunits of the Bcl-2 protein as targets. Using 19F NMR and a specific fragment library (Bionet) with fluorinated compounds we can successfully identify various binders and validate our strategy in the hunt for novel Bcl-2 selective cancer drug strategies to treat currently incurable Bcl-2 sensitive tumors.

Place, publisher, year, edition, pages
MDPI, 2021. Vol. 26, no 5, article id 1467
Keywords [en]
Bcl-2 membrane protein, NMR, drug screening
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-181526DOI: 10.3390/molecules26051467ISI: 000628449100001Scopus ID: 2-s2.0-85103920124OAI: oai:DiVA.org:umu-181526DiVA, id: diva2:1537862
Funder
Swedish Research Council, 2016-06963Swedish Cancer Society, CAN 2015/482The Kempe FoundationsKnut and Alice Wallenberg FoundationAvailable from: 2021-03-17 Created: 2021-03-17 Last updated: 2023-09-05Bibliographically approved

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Ul Mushtaq, AmeeqÅdén, JörgenSparrman, TobiasHedenström, MattiasGröbner, Gerhard

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