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6O0L

crystal structure of BCL-2 G101V mutation with venetoclax

Summary for 6O0L
Entry DOI10.2210/pdb6o0l/pdb
DescriptorApoptosis 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 Keywordsbcl-2, venetoclax, complex, protein-protein interface inhibitor, resistance mutation, fda approved drug complex, apoptosis
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains2
Total formula weight41031.54
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 citationBirkinshaw, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.2 Å)
Structure validation

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건을2024-11-06부터공개중

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