6op0: Difference between revisions
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<StructureSection load='6op0' size='340' side='right'caption='[[6op0]], [[Resolution|resolution]] 2.55Å' scene=''> | <StructureSection load='6op0' size='340' side='right'caption='[[6op0]], [[Resolution|resolution]] 2.55Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6op0]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OP0 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6op0]] is a 3 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=6OP0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OP0 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A7A:(R)- | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.55Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A7A:(~{R})-[1-[(2,5-dimethylphenyl)methyl]-6-(1-methylpyrazol-4-yl)benzimidazol-2-yl]-pyridin-4-yl-methanol'>A7A</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=6op0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6op0 OCA], [https://pdbe.org/6op0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6op0 RCSB], [https://www.ebi.ac.uk/pdbsum/6op0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6op0 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | == 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 == | == 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 == | |||
Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions. | |||
Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer.,O'Connell J, Porter J, Kroeplien B, Norman T, Rapecki S, Davis R, McMillan D, Arakaki T, Burgin A, Fox Iii D, Ceska T, Lecomte F, Maloney A, Vugler A, Carrington B, Cossins BP, Bourne T, Lawson A Nat Commun. 2019 Dec 19;10(1):5795. doi: 10.1038/s41467-019-13616-1. PMID:31857588<ref>PMID:31857588</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6op0" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Tumor necrosis factor 3D structures|Tumor necrosis factor 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Arakaki | [[Category: Arakaki TL]] | ||
[[Category: Ceska | [[Category: Ceska T]] | ||
[[Category: Davies | [[Category: Davies DR]] | ||
[[Category: Edwards | [[Category: Edwards TE]] | ||
[[Category: Fairman | [[Category: Fairman JW]] | ||
[[Category: Foley | [[Category: Foley A]] | ||
Latest revision as of 15:57, 6 November 2024
Asymmetric hTNF-alphaAsymmetric hTNF-alpha
Structural highlights
DiseaseTNFA_HUMAN Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM: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). FunctionTNFA_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.[1] The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.[2] Publication Abstract from PubMedTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions. Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer.,O'Connell J, Porter J, Kroeplien B, Norman T, Rapecki S, Davis R, McMillan D, Arakaki T, Burgin A, Fox Iii D, Ceska T, Lecomte F, Maloney A, Vugler A, Carrington B, Cossins BP, Bourne T, Lawson A Nat Commun. 2019 Dec 19;10(1):5795. doi: 10.1038/s41467-019-13616-1. PMID:31857588[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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