8DSF

Structure of cIAP1 with BCCov

Summary for 8DSF

• Entry DOI: 10.2210/pdb8dsf/pdb
• Descriptor: Baculoviral IAP repeat-containing protein 2, ZINC ION, (4S)-4-[2-(2-{4-[(2E)-4-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}-4-oxobut-2-en-1-yl]piperazin-1-yl}ethoxy)acetamido]-1-{(2S)-2-cyclohexyl-2-[(N-methyl-L-alanyl)amino]acetyl}-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-L-prolinamide unbound form, ... (4 entities in total)
• Functional Keywords: degrader, inhibitor of apoptosis, e3 ligase, apoptosis
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 49962.01

Authors

Schiemer, J.S.,Calabrese, M.F. (deposition date: 2022-07-22, release date: 2023-03-08, Last modification date: 2024-05-01)

Primary citation

Schiemer, J.,Maxwell, A.,Horst, R.,Liu, S.,Uccello, D.P.,Borzilleri, K.,Rajamohan, N.,Brown, M.F.,Calabrese, M.F.
A covalent BTK ternary complex compatible with targeted protein degradation.
Nat Commun, 14:1189-1189, 2023

PubMed Abstract: Targeted protein degradation using heterobifunctional chimeras holds the potential to expand target space and grow the druggable proteome. Most acutely, this provides an opportunity to target proteins that lack enzymatic activity or have otherwise proven intractable to small molecule inhibition. Limiting this potential, however, is the remaining need to develop a ligand for the target of interest. While a number of challenging proteins have been successfully targeted by covalent ligands, unless this modification affects form or function, it may lack the ability to drive a biological response. Bridging covalent ligand discovery with chimeric degrader design has emerged as a potential mechanism to advance both fields. In this work, we employ a set of biochemical and cellular tools to deconvolute the role of covalent modification in targeted protein degradation using Bruton's tyrosine kinase. Our results reveal that covalent target modification is fundamentally compatible with the protein degrader mechanism of action.

PubMed: 36864023
DOI: 10.1038/s41467-023-36738-z

Experimental method

X-RAY DIFFRACTION (1.5 Å)