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==Cryo-EM structure of TNF-alpha in complex with two anti-TNF-alpha nanobodies, TNF30, derived from the TNF-alpha inhibitor Ozoralizumab (OZR)==
<StructureSection load='21tw' size='340' side='right'caption='[[21tw]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[21tw]] is a 4 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=21TW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=21TW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.43&#8491;</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=21tw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=21tw OCA], [https://pdbe.org/21tw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=21tw RCSB], [https://www.ebi.ac.uk/pdbsum/21tw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=21tw 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> 
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== Publication Abstract from PubMed ==
Ozoralizumab (OZR) is a next-generation TNF inhibitor composed of two identical humanized anti-TNFalpha NANOBODY(R) molecules (TNF30s) recombinantly linked via one humanized anti-human serum albumin (HSA) NANOBODY(R) molecule (ALB8) and two peptide linkers. OZR is designed as a unique format to exert potent inhibitory effects against TNFalpha with long plasma half-life. However, the three-dimensional structure of OZR-TNFalpha-HSA complex has not yet been elucidated, and a complete understanding of its interaction mechanism with TNFalpha is yet to be gained. In this study, we successfully observed the formation of the OZR-TNFalpha-HSA ternary complex by single-particle cryo-electron microscopy. The single-particle analysis revealed that the two TNF30 molecules of OZR simultaneously bind bivalently to TNFalpha in a 1:1-bivalent binding mode, while the ALB8 molecule binds to HSA, forming a ternary complex. Thus, OZR exhibits a binding mode significantly different from that of other IgG-type TNFalpha inhibitors. Furthermore, surface plasmon resonance (SPR) analysis demonstrated that the 1:1-bivalent binding mode confers an exceptionally slow dissociation rate, thereby contributing to the potent TNFalpha-neutralizing activity of OZR. These findings not only lend support to the favorable clinical efficacy of OZR from a structural standpoint but also lay the foundation for the rational design and development of next-generation TNFalpha inhibitors with enhanced and sustained efficacy.

Cryo-EM elucidates the interaction mechanism of ozoralizumab, a humanized anti-TNFalpha NANOBODY(R) compound.,Mima M, Sato K, Yokoyama T, Mishima-Tsumagari C, Ohnuki T, Tanaka Y, Iwamoto K Biochem Biophys Res Commun. 2026 Jun 4;816:153572. doi: , 10.1016/j.bbrc.2026.153572. Epub 2026 Mar 6. PMID:41935434<ref>PMID:41935434</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 21tw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mima M]]
[[Category: Mishima-Tsumagari C]]
[[Category: Sato K]]
[[Category: Tanaka Y]]