PDBsum entry 1r2h

Apoptosis

PDB id: 1r2h

Contents

Protein chain

142 a.a. *

Waters ×100

* Residue conservation analysis

PDB id:

1r2h

Name:

Apoptosis

Title:

Human bcl-xl containing an ala to leu mutation at position 142

Structure:

Apoptosis regulator bcl-x. Chain: a. Fragment: bcl-xl. Synonym: bcl-2-like 1 protein. Engineered: yes. Mutation: yes

Source:

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

Resolution:

2.20Å R-factor: 0.205 R-free: 0.234

Authors:

J.W.O'Neill,M.K.Manion,C.D.Giedt,K.M.Kim,K.Y.Zhang,D.M.Hockenbery

Key ref:

M.K.Manion et al. (2004). Bcl-XL mutations suppress cellular sensitivity to antimycin A. J Biol Chem, 279, 2159-2165. PubMed id: 14534311 DOI: 10.1074/jbc.M306021200

Date:

26-Sep-03 Release date: 03-Feb-04

Protein chain

Q07817  (B2CL1_HUMAN) -  Bcl-2-like protein 1 from Homo sapiens

Seq: 233 a.a.

Struc: 142 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1074/jbc.M306021200

J Biol Chem 279:2159-2165 (2004)

PubMed id: 14534311

Bcl-XL mutations suppress cellular sensitivity to antimycin A.

M.K.Manion, J.W.O'Neill, C.D.Giedt, K.M.Kim, K.Y.Zhang, D.M.Hockenbery.

ABSTRACT

Cells expressing high levels of the BCL-X(L) anti-apoptotic protein are preferentially killed by the mitochondrial inhibitor antimycin A (AA). Computational modeling predicts a binding site for AA in the extended hydrophobic groove on BCL-X(L), previously identified as an interface for dimerization to BAX and related proapoptotic proteins. Here, we identify BCL-X(L) hydrophobic groove mutants with normal cellular anti-apoptotic function but suppressed sensitivity to AA. The LD(50) of AA for cells expressing BCL-X(L) mutants directly correlates with the measured in vitro dissociation constants for AA binding. These results indicate that BCL-X(L) is a principal target mediating AA cytotoxicity.

Selected figure(s)

Figure 1.
FIG. 1. Position of BCL-X[L] hydrophobic groove mutations relative to predicted antimycin A[1] binding site. Molecular surface of BCL-X[L] with modeled antimycin A molecule. The Glu-92 (brown) carbonyl oxygen and side chains of Phe-97 (magenta), Ala-142 (purple), and Phe-146 (orange) contact antimycin A[1] in the docking model.

Figure 6.
FIG. 6. Alignments of side chain mutations on BCL-X[L]( C) structure (1BXL [PDB] ) used as docking target for AA[1]. a, alignments of BCL-X[L]( C) structure in free (green) and BAK-BH3-bound (black) conformations. The modeled AA[1] (light green) is shown in place of BAK-BH3 in binding pocket. The C RMSD for residues Glu-92, Phe-97, Ala-142, and Phe-146 is 1.3 Å, whereas overall C RMSD is 2.5 Å. b-d, modeling of mutations into hydrophobic groove of 1BXL [PDB] . Yellow stars indicate clashing contacts. b, F97W (purple) makes two moderate clashing contacts, each at 2.6 Å. c, the A142L mutation (magenta) makes an extreme clashing contact with CD1 to O8 of AA[1] at 1.2 Å. d, although Phe-146 makes two van der Waals contacts with the C27 of AA[1] the F146L mutation (orange) only makes one contact from CD1 (3.4 Å). Nitrogen atoms are colored blue, and oxygen atoms are colored red.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 2159-2165) copyright 2004.

Figures were selected by an automated process.