 |
PDBsum entry 1r2h
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Bcl-Xl mutations suppress cellular sensitivity to antimycin a.
|
|
|
Authors
|
|
M.K.Manion,
J.W.O'Neill,
C.D.Giedt,
K.M.Kim,
K.Y.Zhang,
D.M.Hockenbery.
|
|
|
Ref.
|
|
J Biol Chem, 2004,
279,
2159-2165.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
