Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes.

Autor: Schiemer J; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Horst R; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Meng Y; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Montgomery JI; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Xu Y; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Feng X; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Borzilleri K; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Uccello DP; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Leverett C; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Brown S; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Che Y; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Brown MF; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Hayward MM; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Gilbert AM; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Noe MC; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA., Calabrese MF; Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA. matthew.calabrese@pfizer.com.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2021 Feb; Vol. 17 (2), pp. 152-160. Date of Electronic Publication: 2020 Nov 16.
DOI: 10.1038/s41589-020-00686-2
Abstrakt: Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Advancing from initial chemical tools, protein degraders represent a mechanism of growing interest in drug discovery. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist, including a near absence of studies on one of the most widely co-opted E3s, cellular inhibitor of apoptosis 1 (cIAP1). In this work, we use a combination of biochemical, biophysical and structural studies to characterize degrader-mediated ternary complexes of Bruton's tyrosine kinase and cIAP1. Our results reveal new insights from unique ternary complex structures and show that increased ternary complex stability or rigidity need not always correlate with increased degradation efficiency.
Databáze: MEDLINE
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