6x86: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal Structure of TNFalpha with indolinone compound 11== | ==Crystal Structure of TNFalpha with indolinone compound 11== | ||
<StructureSection load='6x86' size='340' side='right'caption='[[6x86]]' scene=''> | <StructureSection load='6x86' size='340' side='right'caption='[[6x86]], [[Resolution|resolution]] 2.93Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6X86 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6x86]] is a 6 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=6X86 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6X86 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.93Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UTY:3-[(6-{2-[(3R)-4-(hydroxyacetyl)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-2,2-dimethyl-3-oxo-2,3-dihydro-1H-indol-1-yl)methyl]pyridine-2-carbonitrile'>UTY</scene></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=6x86 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x86 OCA], [https://pdbe.org/6x86 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x86 RCSB], [https://www.ebi.ac.uk/pdbsum/6x86 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x86 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN] Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:[https://omim.org/entry/607507 607507]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN] Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.<ref>PMID:16829952</ref> The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.<ref>PMID:16829952</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Tumor necrosis factor alpha (TNFalpha) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-kappaB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFalpha has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFalpha has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFalpha ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFalpha antibody. | |||
Development of Orally Efficacious Allosteric Inhibitors of TNFalpha via Fragment-Based Drug Design.,Dietrich JD, Longenecker KL, Wilson NS, Goess C, Panchal SC, Swann SL, Petros AM, Hobson AD, Ihle D, Song D, Richardson P, Comess KM, Cox PB, Dombrowski A, Sarris K, Donnelly-Roberts DL, Duignan DB, Gomtsyan A, Jung P, Krueger AC, Mathieu S, McClure A, Stoll VS, Wetter J, Mankovich JA, Hajduk PJ, Vasudevan A, Stoffel RH, Sun C J Med Chem. 2020 Dec 30. doi: 10.1021/acs.jmedchem.0c01280. PMID:33378180<ref>PMID:33378180</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6x86" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Longenecker KL]] | [[Category: Longenecker KL]] | ||
[[Category: Stoll VS]] | [[Category: Stoll VS]] | ||