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PDBsum entry 2gtk
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Transcription regulator
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PDB id
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2gtk
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Contents |
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* Residue conservation analysis
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PDB id:
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Transcription regulator
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Title:
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Structure-based design of indole propionic acids as novel pparag co- agonists
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Structure:
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Peroxisome proliferator-activated receptor gamma. Chain: a. Synonym: pparg-lbd. Ppar-gamma. Engineered: yes. Decamer from nuclear receptor coactivator 1. Chain: b. Fragment: residues 631-640. Engineered: yes. Other_details: full protein is transferase, 2.3.1.48
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: pparg, nr1c3. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: this sequence occurs naturally in homo sapiens
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Biol. unit:
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Dimer (from
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Resolution:
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2.10Å
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R-factor:
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0.198
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R-free:
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0.261
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Authors:
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B.Kuhn,H.Hilpert,J.Benz,A.Binggeli,U.Grether,R.Humm,H.-P.Maerki, M.Meyer,P.Mohr
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Key ref:
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B.Kuhn
et al.
(2006).
Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists.
Bioorg Med Chem Lett,
16,
4016-4020.
PubMed id:
DOI:
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Date:
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28-Apr-06
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Release date:
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26-Sep-06
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PROCHECK
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Headers
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References
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P37231
(PPARG_HUMAN) -
Peroxisome proliferator-activated receptor gamma from Homo sapiens
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Seq:
Struc:
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505 a.a.
258 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
16:4016-4020
(2006)
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PubMed id:
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Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists.
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B.Kuhn,
H.Hilpert,
J.Benz,
A.Binggeli,
U.Grether,
R.Humm,
H.P.Märki,
M.Meyer,
P.Mohr.
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ABSTRACT
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In the quest for novel PPARalpha/gamma co-agonists as putative drugs for the
treatment of type 2 diabetes and dyslipidemia, we have used a structure-based
design approach to identify propionic acids with a 1,5-disubstituted indole
scaffold as potent PPARalpha/gamma activators. Compounds 13, 24, and 28 are
examples of submicromolar dual agonists with different alpha/gamma EC50 ratios
that are selective against the delta-isoform. Analysis of the X-ray complex
structure of PPARgamma with the indole propionic acid 13 provides a
rationalization for some of the observed SAR.
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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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B.O.Al-Najjar,
H.A.Wahab,
T.S.Tengku Muhammad,
A.C.Shu-Chien,
N.A.Ahmad Noruddin,
and
M.O.Taha
(2011).
Discovery of new nanomolar peroxisome proliferator-activated receptor γ activators via elaborate ligand-based modeling.
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Eur J Med Chem,
46,
2513-2529.
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Y.Bhurruth-Alcor,
T.Røst,
M.R.Jorgensen,
C.Kontogiorgis,
J.Skorve,
R.G.Cooper,
J.M.Sheridan,
W.D.Hamilton,
J.R.Heal,
R.K.Berge,
and
A.D.Miller
(2011).
Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program protobuild.
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Org Biomol Chem,
9,
1169-1188.
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S.N.Lewis,
J.Bassaganya-Riera,
and
D.R.Bevan
(2010).
Virtual Screening as a Technique for PPAR Modulator Discovery.
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PPAR Res,
2010,
861238.
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E.Proschak,
K.Sander,
H.Zettl,
Y.Tanrikulu,
O.Rau,
P.Schneider,
M.Schubert-Zsilavecz,
H.Stark,
and
G.Schneider
(2009).
From molecular shape to potent bioactive agents II: fragment-based de novo design.
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ChemMedChem,
4,
45-48.
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U.Grether,
A.Bénardeau,
J.Benz,
A.Binggeli,
D.Blum,
H.Hilpert,
B.Kuhn,
H.P.Märki,
M.Meyer,
P.Mohr,
K.Püntener,
S.Raab,
A.Ruf,
and
D.Schlatter
(2009).
Design and biological evaluation of novel, balanced dual PPARalpha/gamma agonists.
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ChemMedChem,
4,
951-956.
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PDB codes:
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A.S.Felts,
B.S.Siegel,
S.M.Young,
C.W.Moth,
T.P.Lybrand,
A.J.Dannenberg,
L.J.Marnett,
and
K.Subbaramaiah
(2008).
Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition.
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J Med Chem,
51,
4911-4919.
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C.Giaginis,
S.Theocharis,
and
A.Tsantili-Kakoulidou
(2008).
Quantitative structure-activity relationships for PPAR-gamma binding and gene transactivation of tyrosine-based agonists using multivariate statistics.
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Chem Biol Drug Des,
72,
257-264.
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D.Genest,
N.Garnier,
A.Arrault,
C.Marot,
L.Morin-Allory,
and
M.Genest
(2008).
Ligand-escape pathways from the ligand-binding domain of PPARgamma receptor as probed by molecular dynamics simulations.
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Eur Biophys J,
37,
369-379.
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K.U.Wendt,
M.S.Weiss,
P.Cramer,
and
D.W.Heinz
(2008).
Structures and diseases.
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Nat Struct Mol Biol,
15,
117-120.
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L.Michalik,
V.Zoete,
G.Krey,
A.Grosdidier,
L.Gelman,
P.Chodanowski,
J.N.Feige,
B.Desvergne,
W.Wahli,
and
O.Michielin
(2007).
Combined simulation and mutagenesis analyses reveal the involvement of key residues for peroxisome proliferator-activated receptor alpha helix 12 dynamic behavior.
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J Biol Chem,
282,
9666-9677.
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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
codes are
shown on the right.
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Links
