6b8y: Difference between revisions

← Older edit Newer edit →

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 3: / Line 3: @@
 <StructureSection load='6b8y' size='340' side='right' caption='[[6b8y]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6b8y]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B8Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B8Y FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6b8y]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B8Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B8Y FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D0A:N-(3-fluoropyridin-4-yl)-2-[6-(trifluoromethyl)pyridin-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine'>D0A</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TGFBR1, ALK5, SKR4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.30 2.7.11.30] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6b8y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b8y OCA], [http://pdbe.org/6b8y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b8y RCSB], [http://www.ebi.ac.uk/pdbsum/6b8y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b8y ProSAT]</span></td></tr>
@@ Line 12: / Line 13: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.<ref>PMID:7774578</ref> <ref>PMID:8752209</ref> <ref>PMID:8980228</ref> <ref>PMID:9346908</ref> <ref>PMID:15761148</ref> <ref>PMID:16754747</ref> <ref>PMID:18758450</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The TGFbeta-TGFbetaR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFbetaR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFbetaRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent=0.14nM), long residence time (T1/2&gt;120min) and significantly improved potency in the PSMAD cellular assay (IC50=24nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFbeta-stimulated phospho-SMAD was observed in primary human T cells.
+Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGFbetaRI).,Harikrishnan LS, Warrier J, Tebben AJ, Tonukunuru G, Madduri SR, Baligar V, Mannoori R, Seshadri B, Rahaman H, Arunachalam PN, Dikundwar AG, Fink BE, Fargnoli J, Fereshteh M, Fan Y, Lippy J, Ho CP, Wautlet B, Sheriff S, Ruzanov M, Borzilleri RM Bioorg Med Chem. 2018 Mar 1;26(5):1026-1034. doi: 10.1016/j.bmc.2018.01.014. Epub, 2018 Jan 31. PMID:29422332<ref>PMID:29422332</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6b8y" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Receptor protein serine/threonine kinase]]
 [[Category: Sheriff, S]]