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PDBsum entry 3dtc
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* Residue conservation analysis
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PDB id:
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Transferase
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Title:
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Crystal structure of mixed-lineage kinase mlk1 complexed with compound 16
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Structure:
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Mitogen-activated protein kinase kinase kinase 9. Chain: a. Synonym: mixed lineage kinase 1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: map3k9, mlk1, prke1. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.60Å
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R-factor:
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0.218
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R-free:
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0.282
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Authors:
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A.A.Fedorov,E.V.Fedorov,S.L.Meyer,R.L.Hudkins,S.C.Almo
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Key ref:
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R.L.Hudkins
et al.
(2008).
Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.
J Med Chem,
51,
5680-5689.
PubMed id:
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Date:
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14-Jul-08
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Release date:
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31-Mar-09
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PROCHECK
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Headers
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References
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P80192
(M3K9_HUMAN) -
Mitogen-activated protein kinase kinase kinase 9 from Homo sapiens
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Seq:
Struc:
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1104 a.a.
245 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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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.2.7.11.25
- mitogen-activated protein kinase kinase kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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J Med Chem
51:5680-5689
(2008)
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PubMed id:
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Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.
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R.L.Hudkins,
J.L.Diebold,
M.Tao,
K.A.Josef,
C.H.Park,
T.S.Angeles,
L.D.Aimone,
J.Husten,
M.A.Ator,
S.L.Meyer,
B.P.Holskin,
J.T.Durkin,
A.A.Fedorov,
E.V.Fedorov,
S.C.Almo,
J.R.Mathiasen,
D.Bozyczko-Coyne,
M.S.Saporito,
R.W.Scott,
J.P.Mallamo.
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ABSTRACT
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The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2)
and R(12) positions led to the identification of the first MLK1 and MLK3
subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and
16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater
than 30- to 100-fold selectivity for related family members MLK2 and DLK.
Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical
efficacy model that was comparable to the first-generation pan-MLK inhibitor 1
(CEP-1347). The MLK1 structure-activity relationships were supported by the
first-reported X-ray crystal structure of MLK1 bound with 16.
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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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M.S.Stark,
S.L.Woods,
M.G.Gartside,
V.F.Bonazzi,
K.Dutton-Regester,
L.G.Aoude,
D.Chow,
C.Sereduk,
N.M.Niemi,
N.Tang,
J.J.Ellis,
J.Reid,
V.Zismann,
S.Tyagi,
D.Muzny,
I.Newsham,
Y.Wu,
J.M.Palmer,
T.Pollak,
D.Youngkin,
B.R.Brooks,
C.Lanagan,
C.W.Schmidt,
B.Kobe,
J.P.MacKeigan,
H.Yin,
K.M.Brown,
R.Gibbs,
J.Trent,
and
N.K.Hayward
(2012).
Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing.
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Nat Genet,
44,
165-169.
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S.Velho,
C.Oliveira,
J.Paredes,
S.Sousa,
M.Leite,
P.Matos,
F.Milanezi,
A.S.Ribeiro,
N.Mendes,
D.Licastro,
A.Karhu,
M.J.Oliveira,
M.Ligtenberg,
R.Hamelin,
F.Carneiro,
A.Lindblom,
P.Peltomaki,
S.Castedo,
S.Schwartz,
P.Jordan,
L.A.Aaltonen,
R.M.Hofstra,
G.Suriano,
E.Stupka,
A.M.Fialho,
and
R.Seruca
(2010).
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.
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Hum Mol Genet,
19,
697-706.
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L.K.Chico,
L.J.Van Eldik,
and
D.M.Watterson
(2009).
Targeting protein kinases in central nervous system disorders.
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Nat Rev Drug Discov,
8,
892-909.
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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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