Crystal structure of ABT-737 complexed with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family

Lee, Erinna F.; Czabotar, P.E.; Smith, Brian J.; Deshayes, Kurt; Zobel, Kerry; Colman, Peter M.; Fairlie, W. Douglas

doi:10.1038/sj.cdd.4402178

Cited by 244 publications

(288 citation statements)

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“…60-fold decrease in affinity for Mcl-1 compared with wild-type Bim versus a 3-fold decrease for Bcl-x L ) (25), this mutant still bound Mcl-1 with ϳ470 nM affinity. As a tyrosine side chain bears some resemblance to the terminal chlorophenyl group of ABT-737, we reasoned that a structure of the Bim BH3 domain with the L12Y mutation in complex with Mcl-1 could provide some insights into how ABT-737 could be modified to bind Mcl-1.…”

Section: Resultsmentioning

confidence: 99%

“…In the 26-mer Bim BH3 peptides used here ( 1 DMRPEI-WIAQELRRIGDEFNAYYARR 26 ), these four hydrophobic amino acids are Ile-8, Leu-12, Ile-15, and Phe-19 (shown in bold). The structure of Bcl-x L in complex with ABT-737 demonstrates that the chlorobiphenyl and thiophenyl groups of ABT-737 occupy pockets accommodating Leu-12 and Phe-19 in the Bim BH3 complex (25). In associated saturation mutagenesis studies we also showed that Mcl-1 is highly tolerant of any side-chain substitutions at the h4 residue of Bim (25), consistent with the structure of the Bim⅐Mcl-1 complex which shows that the h4 binding site on Mcl-1 is poorly formed and exposed to solvent compared with the corresponding region on Bcl-x L (5, 7).…”

Section: Resultsmentioning

confidence: 99%

“…We synthesized the compound (W1191542), although with a phenyl group in place of the chlorophenyl (Fig. 2a), as our mutagenesis studies showed that a phenylalanine substitution at Leu-12 in Bim BH3 was better tolerated in Mcl-1 (binding with 10 nM affinity) than the tyrosine substitution (25).…”

Section: Resultsmentioning

confidence: 99%

“…Only ABT-737, developed by Abbott Laboratories (15,23), has been shown to be a bona fide BH3-mimetic (22,24), binding in the same hydrophobic groove of Bcl-x L as do BH3 ligands (25). ABT-263, a molecule in the same chemical class as ABT-737, has shown efficacy as a single agent in cancer cell lines and animal models of cancer (26 -28) and is currently in a phase I/II clinical trial in leukemia and lymphoma patients.…”

mentioning

confidence: 99%

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Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands

Lee

Czabotar

Yang

et al. 2009

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands

Lee

Czabotar

Yang

et al. 2009

Journal of Biological Chemistry

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“…34,35 Similarly, the putative BH3-binding groove of F1L described here may be a valid target for therapies whose mode of action would be to trigger apoptosis in vaccinia virus-infected cells. Although variola virus is essentially eradicated in the community, concerns persist about its re-emergence as a potential bioweapon.…”

Section: Discussionmentioning

confidence: 99%

Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands

et al. 2008

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Apoptosis is an important part of the host's defense mechanism for eliminating invading pathogens. Some viruses express proteins homologous in sequence and function to mammalian pro-survival Bcl-2 proteins. Anti-apoptotic F1L expressed by vaccinia virus is essential for survival of infected cells, but it bears no discernable sequence homology to proteins other than its immediate orthologues in related pox viruses. Here we report that the crystal structure of F1L reveals a Bcl-2-like fold with an unusual N-terminal extension. The protein forms a novel domain-swapped dimer in which the a1 helix is the exchanged domain. Binding studies reveal an atypical BH3-binding profile, with sub-micromolar affinity only for the BH3 peptide of pro-apoptotic Bim and low micromolar affinity for the BH3 peptides of Bak and Bax. This binding interaction is sensitive to F1L mutations within the predicted canonical BH3-binding groove, suggesting parallels between how vaccinia virus F1L and myxoma virus M11L bind BH3 domains. Structural comparison of F1L with other Bcl-2 family members reveals a novel sequence signature that redefines the BH4 domain as a structural motif present in both pro-and anti-apoptotic Bcl-2 members, including viral Bcl-2-like proteins. In higher organisms, programmed cell death (apoptosis) is a prominent feature of the response to viral infection. The central role of the Bcl-2 protein family in maintaining cell survival or driving apoptosis, thereby removing infected, damaged or unwanted cells, is reflected by the expression of sequence, structural and functional orthologues of Bcl-2 by certain viruses. 1 The Bcl-2-related proteins share the presence of one or more of four Bcl-2 homology (BH) domains in their primary sequences and act either to promote cell survival or to counter this. 2 Pro-survival family members such as mammalian Bcl-2, Bcl-x L , Bcl-w, Mcl-1 and A1 block apoptosis until their protective effect is countered by binding of proapoptotic BH3-only proteins, such as Bim, Bad or Noxa. 2,3 Pro-survival Bcl-2 proteins contain multiple BH domains, whereas the distantly related BH3-only proteins contain only the a-helical BH3 domain, which binds a receptor-like groove on the pro-survival proteins, thereby inactivating them. 4,5 Upon activation, pro-apoptotic Bax and Bak, which are essential for apoptosis to proceed, 6 oligomerize to cause organellar damage.The viral Bcl-2-like proteins, including those expressed by adenovirus, Kaposi sarcoma-associated herpesvirus, Epstein-Barr virus (EBV) and g-herpesvirus 68, are all required for successful viral propagation and/or persistence. However, other viruses express anti-apoptotic proteins that are unrelated by sequence to any known cell death regulator. These include the myxoma virus M11L, 7 cytomegalovirus vMIA 8 and vaccinia virus F1L 9 and E3L. 10 Despite the lack of sequence similarity, M11L adopts a Bcl-2-like fold. 11 Moreover, the structure of M11L in complex with the BH3 peptide from Bak revealed that the canonical BH3-binding groove is utilized in...

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Structure and Function of IAP and Bcl‐2 Proteins

Hinds

Mace

Day

2009

Encyclopedia of Life Sciences

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Interactions between pro‐apoptotic and pro‐survival proteins control the apoptotic programme in cells. Regulation of caspases, the proteolytic enzymes that destroy the cell, is critical and the actions of the inhibitor of apoptosis (IAP) and B‐cell lymphoma‐2 (Bcl‐2) proteins control the life–death switch. IAP proteins can inhibit caspases and signal the destruction of regulatory molecules. In contrast, in mammals, the Bcl‐2 family controls mitochondrial integrity and the release of factors that activate caspases or block the action of IAPs. Structures of many of these proteins, and the complexes they form, are now available and underpin current models of apoptosis. Here we review key features of these structures and highlight how these studies have led to the development of antagonist compounds that allow the pro‐survival effects of IAP and Bcl‐2 proteins to be negated. Key Concepts Caspases are kept inactive in healthy cells by the actions of molecules that inhibit their oligomerization and processing. Pro‐survival Bcl‐2 proteins have a hydrophobic BH3‐binding groove that is required for binding both pro‐apoptotic BH3‐only and Bax‐like proteins. Bcl‐2 proteins exhibit conformational plasticity and can adopt distinct conformations that are required for their activity. The IBM‐binding site on the BIR domains is required for direct inhibition of caspases by IAPs. The RING domain of IAP proteins mediates their ubiquitin E3‐ligase activity, and is required for the pro‐apoptotic activity of IAP‐antagonist molecules. Structures of molecules that prevent caspase activation, in complex with their inhibitors, have guided the development of antagonist compounds that have therapeutic potential.

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Crystal structure of ABT-737 complexed with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family

Cited by 244 publications

References 18 publications

Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands

Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands

Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands

Structure and Function of IAP and Bcl‐2 Proteins

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