21tw

Cryo-EM structure of TNF-alpha in complex with two anti-TNF-alpha nanobodies, TNF30, derived from the TNF-alpha inhibitor Ozoralizumab (OZR)

spinqualitylabelsall models 21tw, resolution 2.43Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 21tw is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.43Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease TNFA_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). Function 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. The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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