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PDBsum entry 6acr
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Signaling protein
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PDB id
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6acr
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PDB id:
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Signaling protein
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Title:
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Crystal structure of human alk2 kinase domain with r206h mutation in complex with rk-59638
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Structure:
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Activin receptor type-1. Chain: a, b. Synonym: activin receptor type i,actr-i,activin receptor-like kinase 2,alk-2,serine/threonine-protein kinase receptor r1,skr1,tgf-b superfamily receptor type i,tsr-i. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: acvr1, acvrlk2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
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Resolution:
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2.01Å
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R-factor:
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0.215
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R-free:
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0.257
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Authors:
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N.Sakai,C.Mishima-Tsumagari,T.Matsumoto,M.Shirouzu
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Key ref:
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K.Sekimata
et al.
(2019).
Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H).
Chem Pharm Bull (Tokyo),
67,
224-235.
PubMed id:
DOI:
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Date:
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27-Jul-18
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Release date:
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20-Mar-19
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PROCHECK
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Headers
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References
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Q04771
(ACVR1_HUMAN) -
Activin receptor type-1 from Homo sapiens
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Seq:
Struc:
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509 a.a.
294 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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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.2.7.11.30
- receptor protein serine/threonine kinase.
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Reaction:
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1.
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L-seryl-[receptor-protein] + ATP = O-phospho-L-seryl-[receptor- protein] + ADP + H+
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2.
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L-threonyl-[receptor-protein] + ATP = O-phospho-L-threonyl-[receptor- protein] + ADP + H+
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L-seryl-[receptor-protein]
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+
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ATP
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=
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O-phospho-L-seryl-[receptor- 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-[receptor-protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[receptor- 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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DOI no:
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Chem Pharm Bull (Tokyo)
67:224-235
(2019)
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PubMed id:
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Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H).
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K.Sekimata,
T.Sato,
N.Sakai,
H.Watanabe,
C.Mishima-Tsumagari,
T.Taguri,
T.Matsumoto,
Y.Fujii,
N.Handa,
T.Honma,
A.Tanaka,
M.Shirouzu,
S.Yokoyama,
K.Miyazono,
Y.Hashizume,
H.Koyama.
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ABSTRACT
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Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely
associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP)
and diffuse intrinsic pontine glioma (DIPG), and therefore presents an
attractive target for therapeutic intervention. Through in silico virtual
screenings and structure-activity relationship studies assisted by X-ray
crystallographic analyses, a novel series of bis-heteroaryl pyrazole was
identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit
compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of
ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral
bioavailability.
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Links
