8AV9

INDUCED MYELOID LEUKEMIA CELL DIFFERENTIATION PROTEIN FABCOMPLEX IN COMPLEX WITH COMPOUND 1

Summary for 8AV9

• Entry DOI: 10.2210/pdb8av9/pdb
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Fab Heavy Chain, Fab Light Chain, ... (5 entities in total)
• Functional Keywords: mcl1, fab, macrocycle, mcl1-fab_55_c6his, immune system, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 68647.95

Authors

Hargreaves, D. (deposition date: 2022-08-26, release date: 2023-05-24, Last modification date: 2024-11-13)

Primary citation

Hargreaves, D.,Carbajo, R.J.,Bodnarchuk, M.S.,Embrey, K.,Rawlins, P.B.,Packer, M.,Degorce, S.L.,Hird, A.W.,Johannes, J.W.,Chiarparin, E.,Schade, M.
Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1.
Proc.Natl.Acad.Sci.USA, 120:e2221967120-e2221967120, 2023

PubMed Abstract: The structure-based design of small-molecule inhibitors targeting protein-protein interactions (PPIs) remains a huge challenge as the drug must bind typically wide and shallow protein sites. A PPI target of high interest for hematological cancer therapy is myeloid cell leukemia 1 (Mcl-1), a prosurvival guardian protein from the Bcl-2 family. Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials. Here, we report the crystal structure of the clinical-stage inhibitor AMG-176 bound to Mcl-1 and analyze its interaction along with clinical inhibitors AZD5991 and S64315. Our X-ray data reveal high plasticity of Mcl-1 and a remarkable ligand-induced pocket deepening. Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis demonstrates that such unprecedented induced fit is uniquely achieved by designing highly rigid inhibitors, preorganized in their bioactive conformation. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully.

PubMed: 37186857
DOI: 10.1073/pnas.2221967120

Experimental method

X-RAY DIFFRACTION (1.99 Å)