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PDBsum entry 2fme
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* Residue conservation analysis
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PDB id:
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Cell cycle
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Title:
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Crystal structure of the mitotic kinesin eg5 (ksp) in complex with mg- adp and (r)-4-(3-hydroxyphenyl)-n,n,7,8-tetramethyl-3,4- dihydroisoquinoline-2(1h)-carboxamide
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Structure:
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Kinesin-like protein kif11. Chain: a, b. Fragment: kinesin-motor domain (residues 1-368). Synonym: kinesin-related motor protein eg5, kinesin-like spindle protein hksp, thyroid receptor interacting protein 5, trip5, kinesin- like protein 1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: kif11, eg5, knsl1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.10Å
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R-factor:
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0.280
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R-free:
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0.305
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Authors:
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S.Sheriff
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Key ref:
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C.M.Tarby
et al.
(2006).
Inhibitors of human mitotic kinesin Eg5: characterization of the 4-phenyl-tetrahydroisoquinoline lead series.
Bioorg Med Chem Lett,
16,
2095-2100.
PubMed id:
DOI:
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Date:
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09-Jan-06
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Release date:
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18-Apr-06
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PROCHECK
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Headers
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References
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P52732
(KIF11_HUMAN) -
Kinesin-like protein KIF11 from Homo sapiens
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Seq:
Struc:
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1056 a.a.
321 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Bioorg Med Chem Lett
16:2095-2100
(2006)
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PubMed id:
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Inhibitors of human mitotic kinesin Eg5: characterization of the 4-phenyl-tetrahydroisoquinoline lead series.
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C.M.Tarby,
R.F.Kaltenbach,
T.Huynh,
A.Pudzianowski,
H.Shen,
M.Ortega-Nanos,
S.Sheriff,
J.A.Newitt,
P.A.McDonnell,
N.Burford,
C.R.Fairchild,
W.Vaccaro,
Z.Chen,
R.M.Borzilleri,
J.Naglich,
L.J.Lombardo,
M.Gottardis,
G.L.Trainor,
D.L.Roussell.
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ABSTRACT
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In a high-throughput screening effort, a series of tetrahydroisoquinolines was
identified as modest inhibitors of human Eg5. A medicinal chemistry optimization
effort led to the identification of
R-4-(3-hydroxyphenyl)-N,N-7,8-tetramethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide
(32a) as a potent inhibitor of human Eg5 (ATPase IC50 104 nM) with good
anti-proliferative activity in A2780 cells (IC50 234 nM).
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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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H.Prokopcová,
D.Dallinger,
G.Uray,
H.Y.Kaan,
V.Ulaganathan,
F.Kozielski,
C.Laggner,
and
C.O.Kappe
(2010).
Structure-activity relationships and molecular docking of novel dihydropyrimidine-based mitotic Eg5 inhibitors.
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ChemMedChem,
5,
1760-1769.
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Z.Zhang,
and
M.Shi
(2010).
Gold(I)-catalyzed domino reaction of aziridinyl alkynes.
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Chemistry,
16,
7725-7729.
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C.Jiang,
Q.You,
F.Liu,
W.Wu,
Q.Guo,
J.Chern,
L.Yang,
and
M.Chen
(2009).
Design, synthesis and evaluation of tetrahydroisoquinolines as new kinesin spindle protein inhibitors.
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Chem Pharm Bull (Tokyo),
57,
567-571.
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C.Jiang,
Y.Chen,
X.Wang,
and
Q.You
(2007).
Docking studies on kinesin spindle protein inhibitors: an important cooperative 'minor binding pocket' which increases the binding affinity significantly.
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J Mol Model,
13,
987-992.
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C.Müller,
D.Gross,
V.Sarli,
M.Gartner,
A.Giannis,
G.Bernhardt,
and
A.Buschauer
(2007).
Inhibitors of kinesin Eg5: antiproliferative activity of monastrol analogues against human glioblastoma cells.
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Cancer Chemother Pharmacol,
59,
157-164.
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I.Garcia-Saez,
S.DeBonis,
R.Lopez,
F.Trucco,
B.Rousseau,
P.Thuéry,
and
F.Kozielski
(2007).
Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration.
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J Biol Chem,
282,
9740-9747.
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PDB code:
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M.D.Planas-Silva,
and
I.S.Filatova
(2007).
Estrogen-dependent regulation of Eg5 in breast cancer cells.
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Anticancer Drugs,
18,
773-779.
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T.Usui
(2007).
Actin- and microtubule-targeting bioprobes: their binding sites and inhibitory mechanisms.
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Biosci Biotechnol Biochem,
71,
300-308.
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T.C.Krzysiak,
and
S.P.Gilbert
(2006).
Dimeric Eg5 maintains processivity through alternating-site catalysis with rate-limiting ATP hydrolysis.
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J Biol Chem,
281,
39444-39454.
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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.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
