7jra
From Proteopedia
(Difference between revisions)
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==HUMAN TNF-ALPHA IN COMPLEX WITH 2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol== | ==HUMAN TNF-ALPHA IN COMPLEX WITH 2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol== | ||
| - | <StructureSection load='7jra' size='340' side='right'caption='[[7jra]]' scene=''> | + | <StructureSection load='7jra' size='340' side='right'caption='[[7jra]], [[Resolution|resolution]] 2.10Å' 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=7JRA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7JRA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7jra]] is a 3 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=7JRA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7JRA FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7jra FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jra OCA], [http://pdbe.org/7jra PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7jra RCSB], [http://www.ebi.ac.uk/pdbsum/7jra PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7jra ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=VGY:2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol'>VGY</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TNF, TNFA, TNFSF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7jra FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jra OCA], [http://pdbe.org/7jra PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7jra RCSB], [http://www.ebi.ac.uk/pdbsum/7jra PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7jra ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN]] Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:[http://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 == | ||
| + | [[http://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 == | ||
| + | Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFalpha). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFalpha trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed. | ||
| + | |||
| + | Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFalpha Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches.,Xiao HY, Li N, Duan JJ, Jiang B, Lu Z, Ngu K, Tino J, Kopcho LM, Lu H, Chen J, Tebben AJ, Sheriff S, Chang CY, Yanchunas J Jr, Calambur D, Gao M, Shuster DJ, Susulic V, Xie JH, Guarino VR, Wu DR, Gregor KR, Goldstine CB, Hynes J Jr, Macor JE, Salter-Cid L, Burke JR, Shaw PJ, Dhar TGM J Med Chem. 2020 Dec 1. doi: 10.1021/acs.jmedchem.0c01732. PMID:33261314<ref>PMID:33261314</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7jra" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Sheriff S]] | + | [[Category: Sheriff, S]] |
| + | [[Category: Asymmetric]] | ||
| + | [[Category: Cytokine]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Lymphokine]] | ||
| + | [[Category: Protein-protein interaction inhibitor]] | ||
| + | [[Category: Tnf]] | ||
| + | [[Category: Tumor necrosis factor alpha]] | ||
Revision as of 11:09, 24 December 2020
HUMAN TNF-ALPHA IN COMPLEX WITH 2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol
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