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An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes.
Zhang, Yuanjin; Liu, Zhonglin; Hirschi, Marscha; Brodsky, Oleg; Johnson, Eric; Won, Sang Joon; Nagata, Asako; Bezwada, Divya; Petroski, Matthew D; Majmudar, Jaimeen D; Niessen, Sherry; VanArsdale, Todd; Gilbert, Adam M; Hayward, Matthew M; Stewart, Al E; Nager, Andrew R; Melillo, Bruno; Cravatt, Benjamin F.
Afiliación
  • Zhang Y; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Liu Z; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Hirschi M; Medicine Design, Pfizer Research and Development, Pfizer, Inc., La Jolla, CA, USA.
  • Brodsky O; Medicine Design, Pfizer Research and Development, Pfizer, Inc., La Jolla, CA, USA.
  • Johnson E; Medicine Design, Pfizer Research and Development, Pfizer, Inc., La Jolla, CA, USA.
  • Won SJ; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Nagata A; Medicine Design, Pfizer Research and Development, Pfizer, Inc., La Jolla, CA, USA.
  • Bezwada D; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Petroski MD; Oncology Research and Development, Pfizer, Inc., La Jolla, CA, USA.
  • Majmudar JD; Discovery Sciences, Pfizer Research and Development, Pfizer, Inc., Cambridge, MA, USA.
  • Niessen S; Oncology Research and Development, Pfizer, Inc., La Jolla, CA, USA.
  • VanArsdale T; Belharra Therapeutics, San Diego, CA, USA.
  • Gilbert AM; Oncology Research and Development, Pfizer, Inc., La Jolla, CA, USA.
  • Hayward MM; Discovery Sciences, Pfizer Research and Development, Pfizer, Inc., Groton, CT, USA.
  • Stewart AE; Discovery Sciences, Pfizer Research and Development, Pfizer, Inc., Groton, CT, USA.
  • Nager AR; Magnet Biomedicine, Boston, MA, USA.
  • Melillo B; Medicine Design, Pfizer Research and Development, Pfizer, Inc., La Jolla, CA, USA.
  • Cravatt BF; Oncology Research and Development, Pfizer, Inc., La Jolla, CA, USA.
Nat Chem Biol ; 2024 Sep 18.
Article en En | MEDLINE | ID: mdl-39294320
ABSTRACT
More than half of the ~20,000 protein-encoding human genes have paralogs. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to subsets of paralogous proteins. Here we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs lacking the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we substituted the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-CCNE1-N112C interaction into in vitro NanoBRET (bioluminescence resonance energy transfer) and in cellulo activity-based protein profiling assays capable of identifying compounds that reversibly inhibit both the N112C mutant and wild-type CCNE1CDK2 (cyclin-dependent kinase 2) complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings, thus, show how electrophile-cysteine interactions mapped by chemical proteomics can extend the understanding of protein ligandability beyond covalent chemistry.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos