spacer
spacer

PDBsum entry 1py5
Go to PDB code: 
protein ligands links
Transferase PDB id
1py5

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chain
301 a.a. *
Ligands
SO4
PY1
Waters ×146
* Residue conservation analysis
PDB id:
1py5
Name: Transferase
Title: Crystal structure of tgf-beta receptor i kinase with inhibitor
Structure: Tgf-beta receptor type i. Chain: a. Fragment: truncated kinase domain, residues 175-500. Synonym: tgfr-1, tgf-beta type i receptor, serine/threonine-protein kinase receptor r4, skr4, activin receptor-like kinase 5, alk-5. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: tgfbr1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
2.30Å     R-factor:   0.258     R-free:   0.292
Authors: F.Zhang,J.S.Sawyer
Key ref: J.S.Sawyer et al. (2004). Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg Med Chem Lett, 14, 3581-3584. PubMed id: 15177479 DOI: 10.1016/j.bmcl.2004.04.007
Date:
08-Jul-03     Release date:   13-Jul-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P36897  (TGFR1_HUMAN) -  TGF-beta receptor type-1 from Homo sapiens
Seq:
Struc: 		503 a.a.
301 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.30  - receptor protein serine/threonine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. L-seryl-[receptor-protein] + ATP = O-phospho-L-seryl-[receptor- protein] + ADP + H+
2. L-threonyl-[receptor-protein] + ATP = O-phospho-L-threonyl-[receptor- protein] + ADP + H+
L-seryl-[receptor-protein]
 + ATP
 = O-phospho-L-seryl-[receptor- protein]
 + ADP
 + H(+)
L-threonyl-[receptor-protein]
 + ATP
 = O-phospho-L-threonyl-[receptor- protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1016/j.bmcl.2004.04.007 Bioorg Med Chem Lett 14:3581-3584 (2004)
PubMed id: 15177479  
 
 
Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.
J.S.Sawyer, D.W.Beight, K.S.Britt, B.D.Anderson, R.M.Campbell, T.Goodson, D.K.Herron, H.Y.Li, W.T.McMillen, N.Mort, S.Parsons, E.C.Smith, J.R.Wagner, L.Yan, F.Zhang, J.M.Yingling.
 
  ABSTRACT  
 
We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21129443 G.Giannelli, A.Mazzocca, E.Fransvea, M.Lahn, and S.Antonaci (2011).
Inhibiting TGF-β signaling in hepatocellular carcinoma.
  Biochim Biophys Acta, 1815, 214-223.  
20616810 R.A.Flavell, S.Sanjabi, S.H.Wrzesinski, and P.Licona-Limón (2010).
The polarization of immune cells in the tumour environment by TGFbeta.
  Nat Rev Immunol, 10, 554-567.  
19916703 R.J.Kelly, and J.C.Morris (2010).
Transforming growth factor-beta: a target for cancer therapy.
  J Immunotoxicol, 7, 15-26.  
20383197 S.E.Wang, Y.Yu, T.L.Criswell, L.M.Debusk, P.C.Lin, R.Zent, D.H.Johnson, X.Ren, and C.L.Arteaga (2010).
Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators.
  Oncogene, 29, 3335-3348.  
20419122 S.Jayaswal, M.A.Kamal, R.Dua, S.Gupta, T.Majumdar, G.Das, D.Kumar, and K.V.Rao (2010).
Identification of host-dependent survival factors for intracellular Mycobacterium tuberculosis through an siRNA screen.
  PLoS Pathog, 6, e1000839.  
18841463 A.R.Tan, G.Alexe, and M.Reiss (2009).
Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer?
  Breast Cancer Res Treat, 115, 453-495.  
18621530 G.D.Cuny, P.B.Yu, J.K.Laha, X.Xing, J.F.Liu, C.S.Lai, D.Y.Deng, C.Sachidanandan, K.D.Bloch, and R.T.Peterson (2008).
Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors.
  Bioorg Med Chem Lett, 18, 4388-4392.  
18183478 J.Prakash, M.H.de Borst, A.M.van Loenen-Weemaes, M.Lacombe, F.Opdam, H.van Goor, D.K.Meijer, F.Moolenaar, K.Poelstra, and R.J.Kok (2008).
Cell-specific delivery of a transforming growth factor-beta type I receptor kinase inhibitor to proximal tubular cells for the treatment of renal fibrosis.
  Pharm Res, 25, 2427-2439.  
18185525 N.Kröger, and R.A.Mesa (2008).
Choosing between stem cell therapy and drugs in myelofibrosis.
  Leukemia, 22, 474-486.  
18625725 S.E.Wang, B.Xiang, M.Guix, M.G.Olivares, J.Parker, C.H.Chung, A.Pandiella, and C.L.Arteaga (2008).
Transforming growth factor beta engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab.
  Mol Cell Biol, 28, 5605-5620.  
17937404 T.O.Fischmann, A.Hruza, J.S.Duca, L.Ramanathan, T.Mayhood, W.T.Windsor, H.V.Le, T.J.Guzi, M.P.Dwyer, K.Paruch, R.J.Doll, E.Lees, D.Parry, W.Seghezzi, and V.Madison (2008).
Structure-guided discovery of cyclin-dependent kinase inhibitors.
  Biopolymers, 89, 372-379.
PDB codes: 2r3f 2r3g 2r3h 2r3i 2r3j 2r3k 2r3l 2r3m 2r3n 2r3o 2r3p 2r3q 2r3r
18032975 F.Cervantes, R.Mesa, and G.Barosi (2007).
New and old treatment modalities in primary myelofibrosis.
  Cancer J, 13, 377-383.  
17572636 J.C.Groppe, E.M.Shore, and F.S.Kaplan (2007).
Functional modeling of the ACVR1 (R206H) mutation in FOP.
  Clin Orthop Relat Res, 462, 87-92.  
18043801 T.Persson, C.W.Yde, J.E.Rasmussen, T.L.Rasmussen, B.Guerra, O.G.Issinger, and J.Nielsen (2007).
Pyrazole carboxamides and carboxylic acids as protein kinase inhibitors in aberrant eukaryotic signal transduction: induction of growth arrest in MCF-7 cancer cells.
  Org Biomol Chem, 5, 3963-3970.  
17155901 A.J.Galliher, J.R.Neil, and W.P.Schiemann (2006).
Role of transforming growth factor-beta in cancer progression.
  Future Oncol, 2, 743-763.  
16186809 R.S.Muraoka-Cook, I.Shin, J.Y.Yi, E.Easterly, M.H.Barcellos-Hoff, J.M.Yingling, R.Zent, and C.L.Arteaga (2006).
Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression.
  Oncogene, 25, 3408-3423.  
15657037 J.Y.Yi, I.Shin, and C.L.Arteaga (2005).
Type I transforming growth factor beta receptor binds to and activates phosphatidylinositol 3-kinase.
  J Biol Chem, 280, 10870-10876.  
16004592 M.Lahn, S.Kloeker, and B.S.Berry (2005).
TGF-beta inhibitors for the treatment of cancer.
  Expert Opin Investig Drugs, 14, 629-643.  
15737997 X.Wang, M.M.Mader, J.E.Toth, X.Yu, N.Jin, R.M.Campbell, J.K.Smallwood, M.E.Christe, A.Chatterjee, T.Goodson, C.J.Vlahos, W.F.Matter, and L.J.Bloem (2005).
Complete inhibition of anisomycin and UV radiation but not cytokine induced JNK and p38 activation by an aryl-substituted dihydropyrrolopyrazole quinoline and mixed lineage kinase 7 small interfering RNA.
  J Biol Chem, 280, 19298-19305.  
16183640 e.l.-.S.Akool, A.Doller, R.Müller, P.Gutwein, C.Xin, A.Huwiler, J.Pfeilschifter, and W.Eberhardt (2005).
Nitric oxide induces TIMP-1 expression by activating the transforming growth factor beta-Smad signaling pathway.
  J Biol Chem, 280, 39403-39416.  
15573100 J.M.Yingling, K.L.Blanchard, and J.S.Sawyer (2004).
Development of TGF-beta signalling inhibitors for cancer therapy.
  Nat Rev Drug Discov, 3, 1011-1022.  
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.

 

spacer
spacer