4IEH

Crystal Structure of human Bcl-2 in complex with a small molecule inhibitor targeting Bcl-2 BH3 domain interactions

Summary for 4IEH

• Entry DOI: 10.2210/pdb4ieh/pdb
• Descriptor: Apoptosis regulator Bcl-2, Bcl-2-like protein 1 chimera, N-(6-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-1,1-dioxido-1,2-benzothiazol-3-yl)-4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzenesulfonamide (3 entities in total)
• Functional Keywords: protein-protein interaction, alpha helical, pro-apoptosis, cytochrome c release, caspase activation, bim, bak, bad, puma, apoptosis-inhibitor complex, apoptosis/inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Mitochondrion outer membrane ; Single-pass membrane protein : P10415
• Total number of polymer chains: 1
• Total formula weight: 20514.32

Authors

Xie, X.,Kulathila, R. (deposition date: 2012-12-13, release date: 2013-07-10, Last modification date: 2024-02-28)

Primary citation

Toure, B.B.,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, 4:186-190, 2013

PubMed Abstract: 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.

PubMed: 24900652
DOI: 10.1021/ml300321d

Experimental method

X-RAY DIFFRACTION (2.1 Å)