6fer: Difference between revisions

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 ==Crystal Structure of human DDR2 kinase in complex with 2-[4,5-difluoro-2-oxo-1'-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)spiro[indole-3,4'-piperidine]-1-yl]-N-(2,2,2-trifluoroethyl)acetamide==
-<StructureSection load='6fer' size='340' side='right' caption='[[6fer]], [[Resolution|resolution]] 2.87&Aring;' scene=''>
+<StructureSection load='6fer' size='340' side='right'caption='[[6fer]], [[Resolution|resolution]] 2.87&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6fer]] is a 12 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=6FER OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FER FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6fer]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FER OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FER FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D6Q:2-[4,5-bis(fluoranyl)-2-oxidanylidene-1-(1~{H}-pyrazolo[3,4-b]pyridin-5-ylcarbonyl)spiro[indole-3,4-piperidine]-1-yl]-~{N}-[2,2,2-tris(fluoranyl)ethyl]ethanamide'>D6Q</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.87&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDR2, NTRKR3, TKT, TYRO10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D6Q:2-[4,5-bis(fluoranyl)-2-oxidanylidene-1-(1~{H}-pyrazolo[3,4-b]pyridin-5-ylcarbonyl)spiro[indole-3,4-piperidine]-1-yl]-~{N}-[2,2,2-tris(fluoranyl)ethyl]ethanamide'>D6Q</scene></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-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6fer FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fer OCA], [https://pdbe.org/6fer PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fer RCSB], [https://www.ebi.ac.uk/pdbsum/6fer PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fer ProSAT]</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=6fer FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fer OCA], [http://pdbe.org/6fer PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fer RCSB], [http://www.ebi.ac.uk/pdbsum/6fer PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fer ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/DDR2_HUMAN DDR2_HUMAN]] Defects in DDR2 are the cause of spondyloepimetaphyseal dysplasia short limb-hand type (SEMD-SL) [MIM:[http://omim.org/entry/271665 271665]]. A bone disease characterized by short-limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping.<ref>PMID:20223752</ref> <ref>PMID:19110212</ref>
+[https://www.uniprot.org/uniprot/DDR2_HUMAN DDR2_HUMAN] Defects in DDR2 are the cause of spondyloepimetaphyseal dysplasia short limb-hand type (SEMD-SL) [MIM:[https://omim.org/entry/271665 271665]. A bone disease characterized by short-limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping.<ref>PMID:20223752</ref> <ref>PMID:19110212</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/DDR2_HUMAN DDR2_HUMAN]] Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing.<ref>PMID:9659899</ref> <ref>PMID:16186108</ref> <ref>PMID:16186104</ref> <ref>PMID:17665456</ref> <ref>PMID:18201965</ref> <ref>PMID:20564243</ref> <ref>PMID:20734453</ref> <ref>PMID:20004161</ref>
+[https://www.uniprot.org/uniprot/DDR2_HUMAN DDR2_HUMAN] Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing.<ref>PMID:9659899</ref> <ref>PMID:16186108</ref> <ref>PMID:16186104</ref> <ref>PMID:17665456</ref> <ref>PMID:18201965</ref> <ref>PMID:20564243</ref> <ref>PMID:20734453</ref> <ref>PMID:20004161</ref>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-The importance of DDR1 in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivo model have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitro safety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45 modulates DDR1 phosphorylation in vitro as well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45 preserves renal function and reduces tissue damage in Col4a3-/- mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3-/- mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population.
-DNA-encoded library-derived DDR1 inhibitor prevents fibrosis and renal function loss in a genetic mouse model of Alport syndrome.,Richter H, Satz AL, Bedoucha M, Buettelmann B, Petersen AC, Harmeier A, Hermosilla R, Hochstrasser R, Burger D, Gsell B, Gasser R, Huber S, Hug MN, Kocer B, Kuhn B, Ritter M, Rudolph MG, Weibel F, Molina-David J, Kim JJ, Santos JV, Stihle M, Georges GJ, Bonfil RD, Fridman R, Uhles S, Moll S, Faul C, Fornoni A, Prunotto M ACS Chem Biol. 2018 Nov 19. doi: 10.1021/acschembio.8b00866. PMID:30452219<ref>PMID:30452219</ref>
+==See Also==
+*[[Epithelial discoidin domain-containing receptor|Epithelial discoidin domain-containing receptor]]
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 6fer" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Receptor protein-tyrosine kinase]]
+[[Category: Large Structures]]
-[[Category: Benz, J]]
+[[Category: Benz J]]
-[[Category: Kuhn, B]]
+[[Category: Kuhn B]]
-[[Category: Richter, H]]
+[[Category: Richter H]]
-[[Category: Rudolph, M G]]
+[[Category: Rudolph MG]]
-[[Category: Stihle, M]]
+[[Category: Stihle M]]
-[[Category: Collagen]]
-[[Category: Discoidin domain]]
-[[Category: Receptor tyrosine kinase]]
-[[Category: Rtk]]
-[[Category: Transferase]]