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    1. karim2001khoury 19 Feb 2026
      Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations

      [Paper-level Aggregated] PMCID: PMC6547681

      Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

      Justification: Oncogenic: The G101V mutation in BCL-2 is associated with acquired resistance to venetoclax therapy in patients with chronic lymphocytic leukaemia, indicating its role in promoting cancer progression. Functional: The study describes how the G101V mutation alters the binding affinity of venetoclax to BCL-2, demonstrating a functional impact on drug interaction and resistance mechanisms. Predictive: The identification of the G101V mutation as a factor that reduces venetoclax affinity allows for predictions about patient responses to this therapy, suggesting that its presence may indicate a likelihood of treatment failure. Prognostic: The emergence of the G101V mutation in patients failing venetoclax therapy suggests it may serve as a prognostic marker for treatment outcomes in chronic lymphocytic leukaemia.

      Gene→Variant (gene-first): BCL2(596):E152 BCL2(596):E152A BCL2(596):G101A BCL2(596):G101V BCL2(596):V101 BCL2(596):G101 BCL2(596):F104 BCL2(596):F104L BCL2(596):L104 BCL2(596):F104C

      Genes: BCL2(596)

      Variants: E152 E152A G101A G101V V101 G101 F104 F104L L104 F104C

      CIViC paper-level aggregated PMC6547681
    2. karim2001khoury 19 Feb 2026
      To further investigate this we solved the structure of BCL-2 G101V bound to S55746 (Table 1). We obtained diffraction to 2.0 A in a P 21 spacegroup with two molecules in the asymmetric unit. The BCL-2 G101V:S55746 struct

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the BCL-2 protein to the drug S55746, indicating a change in molecular function related to drug interaction. Oncogenic: The G101V variant is implicated in the context of tumor development as it affects the binding of a therapeutic agent, suggesting its role in cancer progression.

      Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

      Genes: 596

      Variants: E152 E152A G101V V101

      CIViC paragraph-level PMC6547681 Functional Oncogenic
    3. karim2001khoury 19 Feb 2026
      S55746 is another BCL-2 selective antagonist that has progressed to the clinic. The recently disclosed crystal structure of BCL-2 WT bound to S55746 revealed binding to the P1, P2 and P3 pockets, in contrast to venetocla

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the drug S55746, indicating a change in molecular function related to drug interaction. Predictive: The variant G101V is associated with a change in response to the drug S55746, as indicated by the differences in binding affinity and LC50 concentrations, suggesting its role in treatment sensitivity.

      Gene→Variant (gene-first): 596:G101V

      Genes: 596

      Variants: G101V

      CIViC paragraph-level PMC6547681 Functional Predictive
    4. karim2001khoury 19 Feb 2026
      E152 moved into the base of the P2 pocket in the BCL-2 G101V:venetoclax structure (Fig. 2b, c). To test the role of E152 in reducing affinity we generated a BCL-2 G101V/E152A double mutant. Alanine does not have a Cgamma

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the E152A mutation alters the binding affinity of the BCL-2 protein to venetoclax, indicating a change in molecular function related to protein binding. Predictive: The evidence suggests that the E152A mutation, when combined with G101V, restores high affinity binding to venetoclax, which implies a correlation with response to this specific therapy.

      Gene→Variant (gene-first): 596:E152 596:E152A 596:G101A 596:G101V

      Genes: 596

      Variants: E152 E152A G101A G101V

      CIViC paragraph-level PMC6547681 Functional Predictive
    6. karim2001khoury 19 Feb 2026
      SPR experiments were performed using a BIMBH3 or BAXBH3 immobilised sensor surface with BCL-2 mutants as the analyte and determining venetoclax affinity by competition experiments, (Fig. 3, Table 2 and Supplementary Fig.

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses how the BCL-2 mutants, including G101V, F104L, and F104C, exhibit varying affinities for venetoclax, indicating their role in providing resistance to therapy. Functional: The passage describes how the BCL-2 mutants maintain tight binding to BH3 domains, which alters their molecular function and contributes to their ability to prevent apoptosis.

      Gene→Variant (gene-first): 596:F104C 596:F104L 596:G101V

      Genes: 596

      Variants: F104C F104L G101V

      CIViC paragraph-level PMC6547681 Predictive Functional
    7. karim2001khoury 19 Feb 2026
      The crystals of venetoclax complexed with BCL-2 F104L and BCL-2 WT are isomorphous (Table 1). Well-defined electron density for the drug in the mutant complex structure (Supplementary Fig. 1) suggests two conformations f

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the F104L mutation alters the packing environment of the chlorophenyl moiety of the drug, indicating a change in molecular function related to the variant.

      Gene→Variant (gene-first): 596:F104 596:F104L 596:L104

      Genes: 596

      Variants: F104 F104L L104

      CIViC paragraph-level PMC6547681 Functional
    8. karim2001khoury 19 Feb 2026
      To understand how these BCL-2 mutations compromise drug binding we solved crystal structures of both complexes (Table 1 and Fig. 2). The G101V mutation resides on the BCL-2 alpha2 helix packing against the alpha5 helix a

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the G101V mutation alters drug binding by changing the molecular interactions within the BCL-2 structure, indicating an alteration in biochemical function. Predictive: The evidence suggests that the G101V mutation impacts the binding affinity of venetoclax, which correlates with the response to this specific therapy.

      Gene→Variant (gene-first): 596:E152 596:G101 596:G101A 596:G101V

      Genes: 596

      Variants: E152 G101 G101A G101V

      CIViC paragraph-level PMC6547681 Functional Predictive
    9. karim2001khoury 19 Feb 2026
      Crystal structures of BCL-2 with ABT-263 and various analogues of venetoclax have been deposited in the PDB and described in the literature (Fig. 1a, b). One of those analogues is 4-[4-((4'-chloro-3-[2-(dimethylamino)eth

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 3

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 596:F104

      Genes: 596

      Variants: F104

      CIViC paragraph-level PMC6547681
    10. karim2001khoury 19 Feb 2026
      The BCL-2 mutation G101V reduces venetoclax affinity and confers drug resistance in patients with chronic lymphocytic leukaemia. Here, the authors present crystal structures and biochemical analyses of venetoclax bound t

      [Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 2

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The variant G101V is associated with drug resistance to venetoclax in patients, indicating a correlation with treatment response. Functional: The passage discusses the biochemical analyses of the G101V mutant, revealing how it alters the affinity of venetoclax, which relates to its molecular function.

      Gene→Variant (gene-first): 596:G101V

      Genes: 596

      Variants: G101V

      CIViC paragraph-level PMC6547681 Predictive Functional
    11. karim2001khoury 19 Feb 2026
      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 reveale

      [Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the emergence of the G101V mutation in patients failing therapy with venetoclax, indicating a correlation between the variant and resistance to this specific therapy. Functional: The passage describes how the G101V mutation alters the binding of venetoclax to BCL-2, indicating a change in molecular function related to drug resistance.

      Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

      Genes: 596

      Variants: E152 E152A G101V V101

      CIViC paragraph-level PMC6547681 Predictive Functional
    12. karim2001khoury 19 Feb 2026
      To further investigate this we solved the structure of BCL-2 G101V bound to S55746 (Table 1). We obtained diffraction to 2.0 A in a P 21 spacegroup with two molecules in the asymmetric unit. The BCL-2 G101V:S55746 struct

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the BCL-2 protein to the drug S55746, indicating a change in molecular function related to drug interaction. Oncogenic: The G101V variant is implicated in the context of tumor development as it affects the binding of a therapeutic agent, suggesting its role in cancer progression.

      Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

      Genes: 596

      Variants: E152 E152A G101V V101

      CIViC paragraph-level PMC6547681 Functional Oncogenic
    13. karim2001khoury 19 Feb 2026
      S55746 is another BCL-2 selective antagonist that has progressed to the clinic. The recently disclosed crystal structure of BCL-2 WT bound to S55746 revealed binding to the P1, P2 and P3 pockets, in contrast to venetocla

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the drug S55746, indicating a change in molecular function related to drug interaction. Predictive: The variant G101V is associated with a change in response to the drug S55746, as indicated by the differences in binding affinity and LC50 concentrations, suggesting its role in treatment sensitivity.

      Gene→Variant (gene-first): 596:G101V

      Genes: 596

      Variants: G101V

      CIViC paragraph-level PMC6547681 Functional Predictive
    14. karim2001khoury 19 Feb 2026
      E152 moved into the base of the P2 pocket in the BCL-2 G101V:venetoclax structure (Fig. 2b, c). To test the role of E152 in reducing affinity we generated a BCL-2 G101V/E152A double mutant. Alanine does not have a Cgamma

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the E152A mutation alters the binding affinity of the BCL-2 protein to venetoclax, indicating a change in molecular function related to protein binding. Predictive: The evidence suggests that the E152A mutation, when combined with G101V, restores high affinity binding to venetoclax, which implies a correlation with response to this specific therapy.

      Gene→Variant (gene-first): 596:E152 596:E152A 596:G101A 596:G101V

      Genes: 596

      Variants: E152 E152A G101A G101V

      CIViC paragraph-level PMC6547681 Functional Predictive
    16. karim2001khoury 19 Feb 2026
      SPR experiments were performed using a BIMBH3 or BAXBH3 immobilised sensor surface with BCL-2 mutants as the analyte and determining venetoclax affinity by competition experiments, (Fig. 3, Table 2 and Supplementary Fig.

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses how the BCL-2 mutants, including G101V, F104L, and F104C, exhibit varying affinities for venetoclax, indicating their role in providing resistance to therapy. Functional: The passage describes how the BCL-2 mutants maintain tight binding to BH3 domains, which alters their molecular function and contributes to their ability to prevent apoptosis.

      Gene→Variant (gene-first): 596:F104C 596:F104L 596:G101V

      Genes: 596

      Variants: F104C F104L G101V

      CIViC paragraph-level PMC6547681 Predictive Functional
    17. karim2001khoury 19 Feb 2026
      The crystals of venetoclax complexed with BCL-2 F104L and BCL-2 WT are isomorphous (Table 1). Well-defined electron density for the drug in the mutant complex structure (Supplementary Fig. 1) suggests two conformations f

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the F104L mutation alters the packing environment of the chlorophenyl moiety of the drug, indicating a change in molecular function related to the variant.

      Gene→Variant (gene-first): 596:F104 596:F104L 596:L104

      Genes: 596

      Variants: F104 F104L L104

      CIViC paragraph-level PMC6547681 Functional
    18. karim2001khoury 19 Feb 2026
      To understand how these BCL-2 mutations compromise drug binding we solved crystal structures of both complexes (Table 1 and Fig. 2). The G101V mutation resides on the BCL-2 alpha2 helix packing against the alpha5 helix a

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the G101V mutation alters drug binding by changing the molecular interactions within the BCL-2 structure, indicating an alteration in biochemical function. Predictive: The evidence suggests that the G101V mutation impacts the binding affinity of venetoclax, which correlates with the response to this specific therapy.

      Gene→Variant (gene-first): 596:E152 596:G101 596:G101A 596:G101V

      Genes: 596

      Variants: E152 G101 G101A G101V

      CIViC paragraph-level PMC6547681 Functional Predictive
    19. karim2001khoury 19 Feb 2026
      Crystal structures of BCL-2 with ABT-263 and various analogues of venetoclax have been deposited in the PDB and described in the literature (Fig. 1a, b). One of those analogues is 4-[4-((4'-chloro-3-[2-(dimethylamino)eth

      [Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 3

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 596:F104

      Genes: 596

      Variants: F104

      CIViC paragraph-level PMC6547681
    20. karim2001khoury 19 Feb 2026
      The BCL-2 mutation G101V reduces venetoclax affinity and confers drug resistance in patients with chronic lymphocytic leukaemia. Here, the authors present crystal structures and biochemical analyses of venetoclax bound t

      [Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 2

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The variant G101V is associated with drug resistance to venetoclax in patients, indicating a correlation with treatment response. Functional: The passage discusses the biochemical analyses of the G101V mutant, revealing how it alters the affinity of venetoclax, which relates to its molecular function.

      Gene→Variant (gene-first): 596:G101V

      Genes: 596

      Variants: G101V

      CIViC paragraph-level PMC6547681 Predictive Functional
    21. karim2001khoury 19 Feb 2026
      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 reveale

      [Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the emergence of the G101V mutation in patients failing therapy with venetoclax, indicating a correlation between the variant and resistance to this specific therapy. Functional: The passage describes how the G101V mutation alters the binding of venetoclax to BCL-2, indicating a change in molecular function related to drug resistance.

      Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

      Genes: 596

      Variants: E152 E152A G101V V101

      CIViC paragraph-level PMC6547681 Predictive Functional
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    pmc.ncbi.nlm.nih.gov/articles/PMC6547681/pdf/41467_2019_Article_10363.pdf