Allosteric inhibition of antiapoptotic MCL-1
Open accessAbstract
MCL-1 is an antiapoptotic BCL-2 family protein that has emerged as a major pathogenic factor in human cancer. Like BCL-2, MCL-1 bears a surface groove whose function is to sequester the BH3 killer domains of proapoptotic BCL-2 family members, a mechanism harnessed by cancer cells to establish formidable apoptotic blockades. Although drugging the BH3-binding groove has been achieved for BCL-2, translating this approach to MCL-1 has been challenging. Here, we report an alternative mechanism for MCL-1 inhibition by small-molecule covalent modification of C286 at a new interaction site distant from the BH3-binding groove. Our structure-function analyses revealed that the BH3 binding capacity of MCL-1 and its suppression of BAX are impaired by molecular engagement, a phenomenon recapitulated by C286W mutagenic mimicry in vitro and in mouse cells. Thus, we characterize an allosteric mechanism for disrupting the antiapoptotic BH3 binding activity of MCL-1, informing a new strategy for disarming MCL-1 in cancer.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Lee et al. utilized covalent inhibitor MAIM1 (77) which combines with Cys286 to effectively inhibit Mcl-1 activity (IC50 = 450 nm).
“They utilized the covalent inhibitor, MAIM1 (77) (Table 1), which combines with Cys286 of the thalproquinone type, to effectively inhibit Mcl-1 activity (IC50 = 450 nm).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [228]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 52 · Cited by 59
- Authors
- Lee, S., Wales, T. E., Escudero, S., Cohen, D. T., Luccarelli, J., Gallagher, C. G., Cohen, N. A., Huhn, A. J., Bird, G. H., Engen, J. R., & Walensky, L. D.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Northeastern University (US)
- Boston Children's Hospital (US)
- Corresponding author
- Walensky, Loren D
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2016-05-09
- Volume
- 23
- Issue
- 6
- Pages
- 600-607
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC4900187
- OpenAlex
- W2345969009
- Cited by
- 59
- References
- 52
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 3 · 2020: 11 · 2019: 7 · 2018: 5 · 2017: 7 · 2016: 5
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R35CA197583)
- National Institute of General Medical Sciences (R01GM101135, T32GM007753)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Mcl-1, allosteric inhibition, Bcl-2 family proteins, anti-apoptotic proteins, BH3-binding groove, covalent modification, Bax, apoptosis, cancer, structure-function analysis, BH3 mimetics
- MeSH terms
- Protein Domains, Allosteric Regulation, Animals, Cell Line, Humans, Neoplasms, Protein Binding, Protein Conformation, Mutagenesis, Apoptosis, Point Mutation, Proto-Oncogene Proteins c-bcl-2, bcl-2-Associated X Protein, Mice, Small Molecule Libraries, Molecular Dynamics Simulation, Myeloid Cell Leukemia Sequence 1 Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
