6O0L

crystal structure of BCL-2 G101V mutation with venetoclax

Summary for 6O0L

• Entry DOI: 10.2210/pdb6o0l/pdb
• Descriptor: Apoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2, 4-{4-[(4'-chloro-5,5-dimethyl[3,4,5,6-tetrahydro[1,1'-biphenyl]]-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(oxan-4-yl )methyl]amino}phenyl)sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• Functional Keywords: bcl-2, venetoclax, complex, protein-protein interface inhibitor, resistance mutation, fda approved drug complex, apoptosis
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 41031.54

Authors

Birkinshaw, R.W.,Luo, C.S.,Colman, P.M.,Czabotar, P.E. (deposition date: 2019-02-16, release date: 2019-05-22, Last modification date: 2023-10-11)

Primary citation

Birkinshaw, R.W.,Gong, J.N.,Luo, C.S.,Lio, D.,White, C.A.,Anderson, M.A.,Blombery, P.,Lessene, G.,Majewski, I.J.,Thijssen, R.,Roberts, A.W.,Huang, D.C.S.,Colman, P.M.,Czabotar, P.E.
Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations.
Nat Commun, 10:2385-2385, 2019

PubMed Abstract: Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.

PubMed: 31160589
DOI: 10.1038/s41467-019-10363-1

Experimental method

X-RAY DIFFRACTION (2.2 Å)