8udz
From Proteopedia
The Structure of LTBP-49247 Fab Bound to TGFbeta1 Small Latent Complex
Structural highlights
DiseaseTGFB1_HUMAN Defects in TGFB1 are the cause of Camurati-Engelmann disease (CE) [MIM:131300; also known as progressive diaphyseal dysplasia 1 (DPD1). CE is an autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision.[1] [2] [3] [4] [5] FunctionTGFB1_HUMAN Multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGFB1 and have specific receptors for it. It positively and negatively regulates many other growth factors. It plays an important role in bone remodeling as it is a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts. Publication Abstract from PubMedInhibitors of the transforming growth factor-beta (TGF-beta) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-beta homologs has safety liabilities. TGF-beta1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-beta-binding proteins (LTBPs) present TGF-beta1 in the extracellular matrix, and TGF-beta1 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-beta1 presented by LTBPs but did not bind to TGF-beta1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-beta1 that is not accessible on GARP- or LRRC33-presented TGF-beta1, explaining the antibody's selectivity for LTBP-complexed TGF-beta1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-beta1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-beta inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-beta1 as an approach for treating fibrosis. An antibody that inhibits TGF-beta1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis.,Jackson JW, Frederick C Streich Jr, Pal A, Coricor G, Boston C, Brueckner CT, Canonico K, Chapron C, Cote S, Dagbay KB, Danehy FT Jr, Kavosi M, Kumar S, Lin S, Littlefield C, Looby K, Manohar R, Martin CJ, Wood M, Zawadzka A, Wawersik S, Nicholls SB, Datta A, Buckler A, Schurpf T, Carven GJ, Qatanani M, Fogel AI Sci Signal. 2024 Jul 9;17(844):eadn6052. doi: 10.1126/scisignal.adn6052. Epub , 2024 Jul 9. PMID:38980922[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|