4twt: Difference between revisions
New page: '''Unreleased structure''' The entry 4twt is ON HOLD Authors: Luzi, S., Kondo, Y., Bernard, E., Stadler, L., Winter, G., Holliger, P. Description: Human TNFa dimer in complex with the ... |
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==Human TNFa dimer in complex with the semi-synthetic bicyclic peptide M21== | |||
<StructureSection load='4twt' size='340' side='right'caption='[[4twt]], [[Resolution|resolution]] 2.85Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4twt]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TWT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TWT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.85Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=38A:(2,4,6-TRIMETHYLBENZENE-1,3,5-TRIYL)TRIMETHANOL'>38A</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=4twt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4twt OCA], [https://pdbe.org/4twt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4twt RCSB], [https://www.ebi.ac.uk/pdbsum/4twt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4twt ProSAT]</span></td></tr> | |||
</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 == | |||
Macrocyclic peptides are potentially a source of powerful drugs, but their de novo discovery remains challenging. Here we describe the discovery of a high-affinity (Kd = 10 nM) peptide macrocycle (M21) against human tumor necrosis factor-alpha (hTNFalpha), a key drug target in the treatment of inflammatory disorders, directly from diverse semi-synthetic phage peptide repertoires. The bicyclic peptide M21 (ACPPCLWQVLC) comprises two loops covalently anchored to a 2,4,6-trimethyl-mesitylene core and upon binding induces disassembly of the trimeric TNFalpha cytokine into dimers and monomers. A 2.9 A crystal structure of the M21/hTNFalpha complex reveals the peptide bound to a hTNFalpha dimer at a normally buried epitope in the trimer interface overlapping the binding site of a previously discovered small molecule ligand (SPD304), which also induces TNF trimer dissociation and synergizes with M21 in the inhibition of TNFalpha cytotoxicity. The discovery of M21 underlines the potential of semi-synthetic bicyclic peptides as ligands for the discovery of cryptic epitopes, some of which are poorly accessible to antibodies. | |||
Subunit disassembly and inhibition of TNFalpha by a semi-synthetic bicyclic peptide.,Luzi S, Kondo Y, Bernard E, Stadler LK, Vaysburd M, Winter G, Holliger P Protein Eng Des Sel. 2015 Feb;28(2):45-52. doi: 10.1093/protein/gzu055. PMID:25614525<ref>PMID:25614525</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4twt" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Tumor necrosis factor 3D structures|Tumor necrosis factor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Bernard E]] | |||
[[Category: Holliger P]] | |||
[[Category: Kondo Y]] | |||
[[Category: Luzi S]] | |||
[[Category: Stadler L]] | |||
[[Category: Winter G]] | |||