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PDBsum entry 2jbp
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Contents |
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(+ 3 more)
283 a.a.
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225 a.a.
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265 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural basis for a high affinity inhibitor bound to protein kinase mk2.
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Authors
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R.C.Hillig,
U.Eberspaecher,
F.Monteclaro,
M.Huber,
D.Nguyen,
A.Mengel,
B.Muller-Tiemann,
U.Egner.
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Ref.
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J Mol Biol, 2007,
369,
735-745.
[DOI no: ]
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PubMed id
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Abstract
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The Ser/Thr protein kinase MAPKAP kinase 2 (MK2) plays a crucial role in
inflammation. We determined the structure of the kinase domain of MK2 in complex
with a low molecular mass inhibitor in two different crystal forms, obtained
from soaking and co-crystallization. To our knowledge, these are the first
structures of MK2 showing the binding mode of an inhibitor with high binding
affinity (IC50 8.5 nM). The two crystal forms revealed conformational
flexibility in the binding site and extend the experimental basis for rational
drug design. Crystal form-1 contained one MK2 molecule per asymmetric unit.
Form-2 contained 12 molecules, which arrange into two different types of MK2
trimers. One of them may serve as a model for an intermediate state during
substrate phosphorylation, as each MK2 monomer places its activation segment
into the substrate peptide binding groove of the trimer neighbor.
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Figure 2.
Figure 2. MK2 crystal forms and electron density for
compound-1. MK2 crystals and 2F[o]–F[c] electron density maps
(contoured at 1.3 σ) for the inhibitor, in (a) for the cubic
crystal form-1, in (b) for the orthorhombic crystal form-2
(molecule A). Despite the low resolution, the ligand could be
placed unequivocally in both crystal forms.
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Figure 4.
Figure 4. Stereo representation of compound-1 bound to the
ATP-binding site of MK2. Inhibitor and interacting residues
shown in stick representation and atom colors (inhibitor carbon
atoms in green). In (a) crystal form-1, in (b) molecule-A of
crystal form-2. Black dotted lines represent hydrogen bonds.
Thick orange dotted lines indicate π–π stacking between
compound-1 and Asp142, and two weak hydrogen bonds
(C-H···O to Glu139 in (a) and (b) and
N-H···π to Asp207 in (b)).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2007,
369,
735-745)
copyright 2007.
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Secondary reference #1
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Title
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Identifying protein construct variants with increased crystallization propensity--A case study.
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Authors
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G.A.Malawski,
R.C.Hillig,
F.Monteclaro,
U.Eberspaecher,
A.A.Schmitz,
K.Crusius,
M.Huber,
U.Egner,
P.Donner,
B.Müller-Tiemann.
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Ref.
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Protein Sci, 2006,
15,
2718-2728.
[DOI no: ]
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PubMed id
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