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PDBsum entry 1b6c
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Complex (isomerase/protein kinase)
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PDB id
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1b6c
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the cytoplasmic domain of the type i tgf beta receptor in complex with fkbp12.
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Authors
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M.Huse,
Y.G.Chen,
J.Massagué,
J.Kuriyan.
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Ref.
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Cell, 1999,
96,
425-436.
[DOI no: ]
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PubMed id
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Abstract
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Activation of the type I TGFbeta receptor (TbetaR-I) requires phosphorylation of
a regulatory segment known as the GS region, located upstream of the
serine/threonine kinase domain in the cytoplasmic portion of the receptor. The
crystal structure of a fragment of unphosphorylated TbetaR-I, containing both
the GS region and the catalytic domain, has been determined in complex with the
FK506-binding protein FKBP12. TbetaR-I adopts an inactive conformation that is
maintained by the unphosphorylated GS region. FKBP12 binds to the GS region of
the receptor, capping the TbetaR-II phosphorylation sites and further
stabilizing the inactive conformation of TbetaR-I. Certain structural features
at the catalytic center of TbetaR-I are characteristic of tyrosine kinases
rather than Ser/Thr kinases.
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Figure 4.
Figure 4. The Inhibited Conformation of T β R-I Is
Maintained by the GS Region and the Activation Segment(A) A
ribbon drawing showing the hydrophobic interactions made between
the GS region helices and the top of the kinase β sheet. T β
R-I is viewed from above the kinase N lobe. Thr-204, the site of
a constitutively activating T β R-I mutation ([55]), is
indicated.(B) A ribbon drawing of the complex showing
interactions between the GS loop and the T β R-I kinase, as
well as contacts formed between FKBP12 and T β R-I. Several
interacting residues are shown, with hydrogen bonding indicated
by dashed purple bonds. The L45 loop is indicated.(C) T β R-I
viewed from an oblique angle above the kinase N lobe. The T β
R-II phosphorylation sites are indicated, as are several
residues involved in ionic or polar interactions that stabilize
the placement of the C helix. The movement of the C helix and
the N lobe β sheet into an active conformation appears to be
blocked by the GS loop and a short stretch within the activation
segment. These two steric blockers have been colored magenta.(D)
The same view as in (C), with a molecular surface representation
of the kinase C lobe. The α C side chains have been included to
indicate the space occupied by the helix. The outward rotation
of the C helix and the N lobe β sheet is blocked by the barrier
created by the activation segment.
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Figure 5.
Figure 5. A Comparison of the FKBP12–FK506 and FKBP12–T
β R-I ComplexesA surface representation of FKBP12 bound to
FK506 is shown to the left ([57]). To the right is shown a
surface representation of FKBP12 bound to the T β R-I GS
region. Leu-195 and Leu-196 are bound in the same hydrophobic
pocket used to engage immunosuppressant.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(1999,
96,
425-436)
copyright 1999.
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