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PDBsum entry 2itk
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Isomerase/isomerase inhibitor
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PDB id
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2itk
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Contents |
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* Residue conservation analysis
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Enzyme class:
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E.C.5.2.1.8
- peptidylprolyl isomerase.
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Reaction:
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[protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)
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Peptidylproline (omega=180)
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=
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peptidylproline (omega=0)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Acs Chem Biol
2:320-328
(2007)
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PubMed id:
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Structural basis for high-affinity peptide inhibition of human Pin1.
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Y.Zhang,
S.Daum,
D.Wildemann,
X.Z.Zhou,
M.A.Verdecia,
M.E.Bowman,
C.Lücke,
T.Hunter,
K.P.Lu,
G.Fischer,
J.P.Noel.
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ABSTRACT
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Human Pin1 is a key regulator of cell-cycle progression and plays
growth-promoting roles in human cancers. High-affinity inhibitors of Pin1 may
provide a unique opportunity for disrupting oncogenic pathways. Here we report
two high-resolution X-ray crystal structures of human Pin1 bound to non-natural
peptide inhibitors. The structures of the bound high-affinity peptides identify
a type-I beta-turn conformation for Pin1 prolyl peptide isomerase domain-peptide
binding and an extensive molecular interface for high-affinity recognition.
Moreover, these structures suggest chemical elements that may further improve
the affinity and pharmacological properties of future peptide-based Pin
inhibitors. Finally, an intramolecular hydrogen bond observed in both peptide
complexes mimics the cyclic conformation of FK506 and rapamycin. Both FK506 and
rapamycin are clinically important inhibitors of other peptidyl-prolyl cis-trans
isomerases. This comparative discovery suggests that a cyclic peptide polyketide
bridge, like that found in FK506 and rapamycin or a similar linkage, may
significantly improve the binding affinity of structure-based Pin1 inhibitors.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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D.Clayton,
I.Hanchapola,
N.Hausler,
S.Unabia,
R.A.Lew,
R.E.Widdop,
A.I.Smith,
P.Perlmutter,
and
M.I.Aguilar
(2011).
β-amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2).
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J Mol Recognit,
24,
235-244.
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T.H.Lee,
C.H.Chen,
F.Suizu,
P.Huang,
C.Schiene-Fischer,
S.Daum,
Y.J.Zhang,
A.Goate,
R.H.Chen,
X.Z.Zhou,
and
K.P.Lu
(2011).
Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function.
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Mol Cell,
42,
147-159.
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G.G.Xu,
and
F.A.Etzkorn
(2010).
Convergent synthesis of alpha-ketoamide inhibitors of Pin1.
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Org Lett,
12,
696-699.
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K.Hong Lim,
C.K.Hsu,
and
S.Park
(2010).
Flow cytometric analysis of genetic FRET detectors containing variable substrate sequences.
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Biotechnol Prog,
26,
1765-1771.
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T.Liu,
Y.Liu,
H.Y.Kao,
and
D.Pei
(2010).
Membrane permeable cyclic peptidyl inhibitors against human Peptidylprolyl Isomerase Pin1.
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J Med Chem,
53,
2494-2501.
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Y.Fujimoto,
T.Shiraki,
Y.Horiuchi,
T.Waku,
A.Shigenaga,
A.Otaka,
T.Ikura,
K.Igarashi,
S.Aimoto,
S.Tate,
and
K.Morikawa
(2010).
Proline cis/trans-isomerase Pin1 regulates peroxisome proliferator-activated receptor gamma activity through the direct binding to the activation function-1 domain.
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J Biol Chem,
285,
3126-3132.
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B.Wu,
M.F.Rega,
J.Wei,
H.Yuan,
R.Dahl,
Z.Zhang,
and
M.Pellecchia
(2009).
Discovery and binding studies on a series of novel Pin1 ligands.
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Chem Biol Drug Des,
73,
369-379.
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S.Daum,
M.Schumann,
S.Mathea,
T.Aumüller,
M.A.Balsley,
S.L.Constant,
B.F.de Lacroix,
F.Kruska,
M.Braun,
and
C.Schiene-Fischer
(2009).
Isoform-specific inhibition of cyclophilins.
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Biochemistry,
48,
6268-6277.
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C.Fila,
C.Metz,
and
P.van der Sluijs
(2008).
Juglone inactivates cysteine-rich proteins required for progression through mitosis.
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J Biol Chem,
283,
21714-21724.
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P.Slama,
I.Filippis,
and
M.Lappe
(2008).
Detection of protein catalytic residues at high precision using local network properties.
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BMC Bioinformatics,
9,
517.
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G.Lippens,
I.Landrieu,
and
C.Smet
(2007).
Molecular mechanisms of the phospho-dependent prolyl cis/trans isomerase Pin1.
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FEBS J,
274,
5211-5222.
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K.P.Lu,
and
X.Z.Zhou
(2007).
The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease.
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Nat Rev Mol Cell Biol,
8,
904-916.
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S.Zhao,
and
F.A.Etzkorn
(2007).
A phosphorylated prodrug for the inhibition of Pin1.
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Bioorg Med Chem Lett,
17,
6615-6618.
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T.R.Hupp,
and
M.Walkinshaw
(2007).
Multienzyme assembly of a p53 transcription complex.
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Nat Struct Mol Biol,
14,
885-887.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
