title: X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death.
abstract: THE Bcl-2 family of proteins regulate programmed cell death by an unknown mechanism. Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-xL (ref. 2). The structures consist of two central, primarily hydrophobic alpha-helices, which are surrounded by amphipathic helices. A 60-residue loop connecting helices alpha1 and alpha2 was found to be flexible and non-essential for anti-apoptotic activity. The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity and form an elongated hydrophobic cleft that may represent the binding site for other Bcl-2 family members. The arrangement of the alpha-helices in Bcl-xL is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins. The structural similarity may provide a clue to the mechanism of action of the Bcl-2 family of proteins.
authors.affiliation: Protein Crystallography, Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Muchmore
authors.forename: M
authors.initials: M
authors.lastname: Sattler
authors.forename: H
authors.initials: H
authors.lastname: Liang
authors.forename: R P
authors.initials: RP
authors.lastname: Meadows
authors.forename: J E
authors.initials: JE
authors.lastname: Harlan
authors.forename: H S
authors.initials: HS
authors.lastname: Yoon
authors.forename: D
authors.initials: D
authors.lastname: Nettesheim
authors.forename: B S
authors.initials: BS
authors.lastname: Chang
authors.forename: C B
authors.initials: CB
authors.lastname: Thompson
authors.forename: S L
authors.initials: SL
authors.lastname: Wong
authors.forename: S L
authors.initials: SL
authors.lastname: Ng
authors.forename: S W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D018360:Crystallography, X-Ray; D004926:Escherichia coli; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein