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PDBsum entry 3mtf
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Contents |
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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 the acvr1 kinase in complex with a 2- aminopyridine inhibitor
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Structure:
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Activin receptor type-1. Chain: a, b. Fragment: kinase domain (unp residues 201-499). Synonym: activin receptor type i, actr-i, serine/threonine-protein kinase receptor r1, skr1, activin receptor-like kinase 2, alk-2, 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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2.15Å
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R-factor:
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0.185
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R-free:
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0.244
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Authors:
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A.Chaikuad,C.Sanvitale,C.Cooper,P.Mahajan,N.Daga,K.Petrie,I.Alfano, P.Canning,T.Krojer,M.Vollmar,S.Knapp,F.Von Delft,J.Weigelt, C.H.Arrowsmith,A.M.Edwards,C.Bountra,A.Bullock,Structural Genomics Consortium (Sgc)
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Key ref:
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C.E.Sanvitale
et al.
(2013).
A new class of small molecule inhibitor of BMP signaling.
Plos One,
8,
e62721.
PubMed id:
DOI:
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Date:
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30-Apr-10
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Release date:
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23-Jun-10
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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.
296 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.2.7.11.30
- 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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Plos One
8:e62721
(2013)
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PubMed id:
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A new class of small molecule inhibitor of BMP signaling.
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C.E.Sanvitale,
G.Kerr,
A.Chaikuad,
M.C.Ramel,
A.H.Mohedas,
S.Reichert,
Y.Wang,
J.T.Triffitt,
G.D.Cuny,
P.B.Yu,
C.S.Hill,
A.N.Bullock.
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ABSTRACT
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Growth factor signaling pathways are tightly regulated by phosphorylation and
include many important kinase targets of interest for drug discovery. Small
molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2
(ACVR1) are needed urgently to treat the progressively debilitating
musculoskeletal disease fibrodysplasia ossificans progressiva (FOP).
Dorsomorphin analogues, first identified in zebrafish, remain the only BMP
inhibitor chemotype reported to date. By screening an assay panel of 250
recombinant human kinases we identified a highly selective 2-aminopyridine-based
inhibitor K02288 with in vitro activity against ALK2 at low nanomolar
concentrations similar to the current lead compound LDN-193189. K02288
specifically inhibited the BMP-induced Smad pathway without affecting TGF-β
signaling and induced dorsalization of zebrafish embryos. Comparison of the
crystal structures of ALK2 with K02288 and LDN-193189 revealed additional
contacts in the K02288 complex affording improved shape complementarity and
identified the exposed phenol group for further optimization of
pharmacokinetics. The discovery of a new chemical series provides an independent
pharmacological tool to investigate BMP signaling and offers multiple
opportunities for pre-clinical development.
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Links
