 |
PDBsum entry 1ir3
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Complex (transferase/substrate)
|
PDB id
|
|
|
|
1ir3
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog.
|
|
|
Author
|
|
S.R.Hubbard.
|
|
|
Ref.
|
|
EMBO J, 1997,
16,
5572-5581.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The crystal structure of the phosphorylated, activated form of the insulin
receptor tyrosine kinase in complex with a peptide substrate and an ATP analog
has been determined at 1.9 A resolution. The activation loop (A-loop) of the
kinase undergoes a major conformational change upon autophosphorylation of
Tyr1158, Tyr1162 and Tyr1163 within the loop, resulting in unrestricted access
of ATP and protein substrates to the kinase active site. Phosphorylated Tyr1163
(pTyr1163) is the key phosphotyrosine in stabilizing the conformation of the
tris-phosphorylated A-loop, whereas pTyr1158 is completely solvent-exposed,
suggesting an availability for interaction with downstream signaling proteins.
The YMXM-containing peptide substrate binds as a short anti-parallel beta-strand
to the C-terminal end of the A-loop, with the methionine side chains occupying
two hydrophobic pockets on the C-terminal lobe of the kinase. The structure thus
reveals the molecular basis for insulin receptor activation via
autophosphorylation, and provides insights into tyrosine kinase substrate
specificity and the mechanism of phosphotransfer.
|
|
|
|
|
|
|
|
Figure 1.
Figure 1 Electron density map of the active site of IRK3P.
Stereo view of a 2F[o] -F[c] map computed at 1.9 Å resolution
and contoured at 1.2  .
Superimposed is the refined atomic model. Carbon atoms are
yellow, oxygen atoms red, nitrogen atoms blue, phosphate atoms
purple, and sulfur atoms green. The red spheres represent water
molecules and the white spheres represent Mg2+ ions. Figure
prepared with SETOR (Evans, 1993).
|
|
Figure 2.
Figure 2 Overall view of IRK3P and comparison with IRK. (A)
Ribbon diagram of the IRK3P structure. The  -helices
are shown in red, the  -strands
in blue, the nucleotide-binding loop in yellow, the catalytic
loop in orange, the activation loop in green, AMP-PNP in black
and the peptide substrate in pink. The termini are denoted by N
and C. (B) Superposition of the C-terminal lobes of IRK and
IRK3P. The backbone representation of IRK/IRK3P is colored
orange/green, with the activation loop colored red/blue. The
axis (black) and arrow (blue) specify the rotation required to
align the N-terminal -sheet
of IRK with that of IRK3P. (C) Superposition of the -sheets
in the N-terminal lobes of IRK and IRK3P. The backbone
representation and carbon atoms of IRK/IRK3P are colored
orange/green, oxygen atoms are red and nitrogen atoms are blue.
(A) and (C) prepared with RIBBONS (Carson, 1991), (B) with GRASP
(Nicholls et al., 1991).
|
|
|
|
|
|
The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(1997,
16,
5572-5581)
copyright 1997.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Crystal structure of the tyrosine kinase domain of the human insulin receptor.
|
|
|
Authors
|
|
S.R.Hubbard,
L.Wei,
L.Ellis,
W.A.Hendrickson.
|
|
|
Ref.
|
|
Nature, 1994,
372,
746-754.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
