| Structural highlights
4ieh is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | Gene: | BCL2, BCL2L, BCL2L1, BCLX (HUMAN) |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[BCL2_HUMAN] Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.
Function
[BCL2_HUMAN] Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).[1]
Publication Abstract from PubMed
Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.
The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.,Toure BB, Miller-Moslin K, Yusuff N, Perez L, Dore M, Joud C, Michael W, DiPietro L, van der Plas S, McEwan M, Lenoir F, Hoe M, Karki R, Springer C, Sullivan J, Levine K, Fiorilla C, Xie X, Kulathila R, Herlihy K, Porter D, Visser M ACS Med Chem Lett. 2013 Jan 4;4(2):186-90. doi: 10.1021/ml300321d. eCollection, 2013 Feb 14. PMID:24900652[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008 Jun 20;30(6):678-88. doi: 10.1016/j.molcel.2008.06.001. PMID:18570871 doi:10.1016/j.molcel.2008.06.001
- ↑ Toure BB, Miller-Moslin K, Yusuff N, Perez L, Dore M, Joud C, Michael W, DiPietro L, van der Plas S, McEwan M, Lenoir F, Hoe M, Karki R, Springer C, Sullivan J, Levine K, Fiorilla C, Xie X, Kulathila R, Herlihy K, Porter D, Visser M. The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions. ACS Med Chem Lett. 2013 Jan 4;4(2):186-90. doi: 10.1021/ml300321d. eCollection, 2013 Feb 14. PMID:24900652 doi:http://dx.doi.org/10.1021/ml300321d
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