6XM2

The structure of the 4A11.v7 antibody in complex with human TGFb2

Summary for 6XM2

• Entry DOI: 10.2210/pdb6xm2/pdb
• Descriptor: 4A11.v7 kappa light chain Fab (VL-CL) humanized, 4A11.v7 heavy chain Fab (VH-CH1) IgG1 humanized, Transforming growth factor beta-2, ... (4 entities in total)
• Functional Keywords: tgfb antibody, cytokine, cytokine-immune system complex, cytokine/immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 12
• Total formula weight: 243111.78

Authors

Lupardus, P.J.,Yin, J.P. (deposition date: 2020-06-29, release date: 2021-07-07, Last modification date: 2024-10-23)

Primary citation

Sun, T.,Huang, Z.,Liang, W.C.,Yin, J.,Lin, W.Y.,Wu, J.,Vernes, J.M.,Lutman, J.,Caplazi, P.,Jeet, S.,Wong, T.,Wong, M.,DePianto, D.J.,Morshead, K.B.,Sun, K.H.,Modrusan, Z.,Vander Heiden, J.A.,Abbas, A.R.,Zhang, H.,Xu, M.,N'Diaye, E.N.,Roose-Girma, M.,Wolters, P.J.,Yadav, R.,Sukumaran, S.,Ghilardi, N.,Corpuz, R.,Emson, C.,Meng, Y.G.,Ramalingam, T.R.,Lupardus, P.,Brightbill, H.D.,Seshasayee, D.,Wu, Y.,Arron, J.R.
TGF beta 2 and TGF beta 3 isoforms drive fibrotic disease pathogenesis.
Sci Transl Med, 13:-, 2021

PubMed Abstract: Transforming growth factor-β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFβ2 and TGFβ3 have not been well characterized. Here, we show that the latent forms of TGFβ2 and TGFβ3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFβ1. Unlike , and expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFβ2 and TGFβ3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFβ isoform-selective antibodies demonstrated that TGFβ2 and TGFβ3 are independently involved in mouse fibrosis models in vivo, and selective TGFβ2 and TGFβ3 inhibition does not lead to the increased inflammation observed with pan-TGFβ isoform inhibition. A cocrystal structure of a TGFβ2-anti-TGFβ2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFβ2 and/or TGFβ3 while sparing TGFβ1 may alleviate fibrosis without toxicity concerns associated with pan-TGFβ blockade.

PubMed: 34349032
DOI: 10.1126/scitranslmed.abe0407

Experimental method

X-RAY DIFFRACTION (1.91 Å)