NMR Solution Structure of a Photoswitchable Apoptosis Activating Bak Peptide Bound to Bcl-xL
Abstract
The Bcl-2 family of proteins includes the major regulators and effectors of the intrinsic apoptosis pathway. Cancers are frequently formed when activation of the apoptosis mechanism is compromised either by misregulated expression of prosurvival family members or, more frequently, by damage to the regulatory pathways that trigger intrinsic apoptosis. Short peptides derived from the pro-apoptotic members of the Bcl-2 family can activate mechanisms that ultimately lead to cell death. The recent development of photocontrolled peptides that are able to change their conformation and activity upon irradiation with an external light source has provided new tools to target cells for apoptosis induction with temporal and spatial control. Here, we report the first NMR solution structure of a photoswitchable peptide derived from the proapoptotic protein Bak in complex with the antiapoptotic protein Bcl-x(L). This structure provides insight into the molecular mechanism, by which the increased affinity of such photopeptides compared to their native forms is achieved, and offers a rationale for the large differences in the binding affinities between the helical and nonhelical states.
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- Authors
- Wysoczanski, P., Mart, R. J., Loveridge, E. J., Williams, C., Whittaker, S. B.-M., Crump, M. P., & Allemann, R. K.
- Affiliations
- School of Chemistry and Cardiff Catalysis Institute, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom
- Cardiff University (GB)
- University of Bristol (GB)
- University of Birmingham (GB)
- Corresponding author
- Allemann, Rudolf K.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-04-25
- Volume
- 134
- Issue
- 18
- Pages
- 7644-7647
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2149676425
- Cited by
- 47
- References
- 34
- Citations by year
- 2026: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 3 · 2015: 9 · 2014: 7 · 2013: 5 · 2012: 1
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- Wellcome Trust (WT082352)
- Engineering and Physical Sciences Research Council (EP/F040954/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Photochromic and Fluorescence Chemistry
- Keywords
- Bcl-xL, Bcl-2 family proteins, photoswitchable peptides, mitochondrial apoptosis, protein-peptide complex, solution structure, binding affinity, photoinduced conformational change
- MeSH terms
- Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, Peptides, Apoptosis, Nuclear Magnetic Resonance, Biomolecular, bcl-2 Homologous Antagonist-Killer Protein, bcl-X Protein
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