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Insight into Functi...
Insight into Functional Membrane Proteins by Solution NMR : The Human Bcl-2 Protein - A Promising Cancer Drug Target
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- Ul Mushtaq, Ameeq (författare)
- Umeå universitet,Kemiska institutionen
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- Ådén, Jörgen, 1980- (författare)
- Umeå universitet,Kemiska institutionen
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- Sparrman, Tobias (författare)
- Umeå universitet,Kemiska institutionen
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- Hedenström, Mattias, 1976- (författare)
- Umeå universitet,Kemiska institutionen
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- Gröbner, Gerhard (författare)
- Umeå universitet,Kemiska institutionen
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(creator_code:org_t)
- 2021-03-08
- 2021
- Engelska.
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Ingår i: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 26:5
- Relaterad länk:
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https://doi.org/10.3...
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https://umu.diva-por... (primary) (Raw object)
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https://www.mdpi.com...
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https://urn.kb.se/re...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Bcl-2 membrane protein
- NMR
- drug screening
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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