9GY3

Crystal structure of CRBNmidi in complex with (S)-dHTC1

This is a non-PDB format compatible entry.

Summary for 9GY3

• Entry DOI: 10.2210/pdb9gy3/pdb
• Descriptor: Protein cereblon, 2-[3-[2-[4-[[(5~{S})-1,3-bis(oxidanylidene)-2,7-diazaspiro[4.4]nonan-7-yl]sulfonylamino]piperidin-1-yl]ethylcarbamoyl]phenyl]-~{N}-cyclobutyl-imidazo[1,2-a]pyridine-6-carboxamide, ZINC ION, ... (4 entities in total)
• Functional Keywords: e3 ligase, tpd, molecular glue, induced proximity, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 76442.00

Authors

Rutter, Z.J.,Shaum, J.B.,Ciulli, A.,Erb, M.A. (deposition date: 2024-10-01, release date: 2025-10-01)

Primary citation

Shaum, J.B.,Munoz I Ordono, M.,Steen, E.A.,Wenge, D.V.,Cheong, H.,Hunkeler, M.,Bilotta, E.M.,Rutter, Z.,Barta, P.A.,Thornhill, A.M.,Milosevich, N.,Hargis, L.M.,Janowski, J.,Bishop, T.R.,Carter, T.R.,da Camara, B.,Hinterndorfer, M.,Dada, L.,He, W.J.,Offensperger, F.,Furihata, H.,Schweber, S.R.,Hatton, C.,Wen, Y.,Cravatt, B.F.,Engle, K.M.,Donovan, K.A.,Melillo, B.,Kitamura, S.,Ciulli, A.,Armstrong, S.A.,Fischer, E.S.,Winter, G.E.,Erb, M.A.
High-throughput diversification of protein-ligand surfaces to discover chemical inducers of proximity.
Biorxiv, 2025

PubMed Abstract: Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of heterobifunctional CIPs, monovalent, molecular glue-like CIPs have relied predominantly on serendipity. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to empirically discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Here, we used sulfur(VI)-fluoride exchange (SuFEx)-based high-throughput chemistry (HTC) to install 3,163 structurally diverse chemical building blocks onto ENL and BRD4 ligands and then screened the crude products for degrader activity. This revealed dHTC1, a potent, selective, and stereochemistry-dependent degrader of ENL. It recruits CRL4 to ENL through an extended interface of protein-protein and protein-ligand contacts, but only after pre-forming the ENL:dHTC1 complex. We also characterized two structurally distinct BRD4 degraders, including dHTC3, a molecular glue that selectively dimerizes the first bromodomain of BRD4 to SCF , an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and actionable cellular effectors of proximity pharmacology.

PubMed: 40950085
DOI: 10.1101/2024.09.30.615685

Experimental method

X-RAY DIFFRACTION (2.5 Å)