PDBsum entry: 1ysw

Apoptosis

PDB id: 1ysw

Contents

Protein chain

164 a.a. *

Ligands

43B

* Residue conservation analysis

PDB id:

1ysw

Name:

Apoptosis

Title:

Solution structure of the anti-apoptotic protein bcl-2 complexed with an acyl-sulfonamide-based ligand

Structure:

Apoptosis regulator bcl-2. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bcl2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

NMR struc:

1 models

Authors:

T.Oltersdorf,S.W.Elmore,A.R.Shoemaker,R.C.Armstrong, D.J.Augeri,B.A.Belli,M.Bruncko,T.L.Deckwerth,J.Dinges, P.J.Hajduk,M.K.Joseph,S.Kitada,S.J.Korsmeyer,A.R.Kunzer, A.Letai,C.Li,M.J.Mitten,D.G.Nettesheim,S.Ng,P.M.Nimmer, J.M.O'Connor,A.Oleksijew,A.M.Petros,J.C.Reed,W.Shen, S.K.Tahir,C.B.Thompson,K.J.Tomaselli,B.Wang,M.D.Wendt, H.Zhang,S.W.Fesik,S.H.Rosenberg

Key ref:

T.Oltersdorf et al. (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 435, 677-681. PubMed id: 15902208 DOI: 10.1038/nature03579

Date:

09-Feb-05 Release date: 07-Jun-05

Protein chain

P10415  (BCL2_HUMAN) -  Apoptosis regulator Bcl-2

Seq: 239 a.a.

Struc: 164 a.a.*

* PDB and UniProt seqs differ at 14 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• Biological process: regulation of apoptosis (1 term)

DOI no: 10.1038/nature03579

Nature 435:677-681 (2005)

PubMed id: 15902208

An inhibitor of Bcl-2 family proteins induces regression of solid tumours.

T.Oltersdorf, S.W.Elmore, A.R.Shoemaker, R.C.Armstrong, D.J.Augeri, B.A.Belli, M.Bruncko, T.L.Deckwerth, J.Dinges, P.J.Hajduk, M.K.Joseph, S.Kitada, S.J.Korsmeyer, A.R.Kunzer, A.Letai, C.Li, M.J.Mitten, D.G.Nettesheim, S.Ng, P.M.Nimmer, J.M.O'Connor, A.Oleksijew, A.M.Petros, J.C.Reed, W.Shen, S.K.Tahir, C.B.Thompson, K.J.Tomaselli, B.Wang, M.D.Wendt, H.Zhang, S.W.Fesik, S.H.Rosenberg.

ABSTRACT

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.

Selected figure(s)

Figure 1.
Figure 1: Generation of ABT-737. a, Connolly surface of the complex of Bcl-X[L] with a Bak-derived peptide (GQVGRQLAIIGDDINR, green) overlaid on the ternary complex of Bcl-X[L] and NMR-based screening leads (orange). Phe 97 is shown in yellow. Residues of the Bak peptide (Asp 83, Leu 78, Ile 85) critical for binding are shown in magenta. b, Connolly surface of the NMR structure of Bcl-X[L] complexed with compound 1. c, Cutaway Connolly surface for the NMR structure of domain III of HSA bound to the thioethylamino-2,4-dimethylphenyl analogue of compound 1. Arrows indicate proposed sites of modification. d, Chemical structure of ABT-737.

Figure 2.
Figure 2: ABT-737 antagonizes anti-apoptotic Bcl-2 family proteins. a, ABT-737 and Bad BH3 peptide do not induce cytochrome c release from wild-type (filled bar) or Bcl-2 transfected (open bar) mitochondria, but antagonize the ability of Bcl-2 to inhibit Bid-mediated cytochrome c release. Data are mean s.d. b -g, Confocal microscopic images of HeLa cells transfected with Bcl-X[L] and GFP-Bcl-G[S] visualized with GFP fluorescence. b, e, Phase-contrast images of untreated cells c, f, Bcl-G[S] fused to GFP displays a punctate pattern coincident with mitochondria. d, g, ABT-737 (100 nM, d) but not the enantiomer (100 nM, g) displaces GFP-labelled Bcl-G[S] from mitochondria.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2005, 435, 677-681) copyright 2005.

Figures were selected by an automated process.