Evidence map›Paper›PMID 38293178›Full record

ArticlebioRxiv : the preprint server for biology2024

Expanding the ligandable proteome by paralog hopping with covalent probes.

Yuanjin Zhang, Zhonglin Liu, Marsha Hirschi, Oleg Brodsky, Eric Johnson, Sang Joon Won, Asako Nagata, Matthew D Petroski, Jaimeen D Majmudar, Sherry Niessen and 7 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed, 7 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 2 institutions in 1 country.

Yuanjin ZhangDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 USA.
Zhonglin LiuDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 USA.
Marsha HirschiMedicine Design, Pfizer Research and Development, Pfizer Inc., La Jolla, CA 92121, USA.
Oleg BrodskyMedicine Design, Pfizer Research and Development, Pfizer Inc., La Jolla, CA 92121, USA.
Eric JohnsonMedicine Design, Pfizer Research and Development, Pfizer Inc., La Jolla, CA 92121, USA.
Sang Joon WonDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 USA.
Asako NagataMedicine Design, Pfizer Research and Development, Pfizer Inc., La Jolla, CA 92121, USA.
Matthew D PetroskiOncology Research and Development, Pfizer Inc., La Jolla, CA 92121, USA.
Jaimeen D MajmudarDiscovery Sciences, Pfizer Research and Development, Pfizer Inc., Cambridge, MA 02139, USA.
Sherry NiessenOncology Research and Development, Pfizer Inc., La Jolla, CA 92121, USA.
Todd VanArsdaleOncology Research and Development, Pfizer Inc., La Jolla, CA 92121, USA.
Adam M GilbertDiscovery Sciences, Pfizer Research and Development, Pfizer Inc., Groton, CT 06340, USA.
Matthew M HaywardDiscovery Sciences, Pfizer Research and Development, Pfizer Inc., Groton, CT 06340, USA.
Al E StewartMedicine Design, Pfizer Research and Development, Pfizer Inc., La Jolla, CA 92121, USA.
Andrew R NagerOncology Research and Development, Pfizer Inc., La Jolla, CA 92121, USA.
Bruno MelilloDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 USA.
Benjamin CravattDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 USA.
Pfizer (United States) · USScripps Research Institute · US

Funding

Chemical Proteomic Platforms for Radically Expanding Cancer DruggabilityR35CA231991 · NCI · SCRIPPS RESEARCH INSTITUTE, THE · PI BENJAMIN F CRAVATT · 2018 to 2026
$9.5M
NCI NIH HHS R35 CA231991
6 · The paper itself

Abstract

More than half of the ~20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling (ABPP) that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-N112C-CCNE1 interaction into a NanoBRET-ABPP assay capable of identifying compounds that reversibly inhibit both N112C- and WT-CCNE1:CDK2 complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings thus provide a roadmap for leveraging electrophile-cysteine interactions to extend the ligandability of the proteome beyond covalent chemistry.

Identifiers

PMID38293178
PMCPMC10827202
OpenAlexW4391050538

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.