8udz

The Structure of LTBP-49247 Fab Bound to TGFbeta1 Small Latent Complex

Structural highlights

8udz is a 6 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:	X-ray diffraction, Resolution 2.21Å
Ligands:	BMA, MAN, NAG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TGFB1_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]

Function

TGFB1_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 PubMed

Inhibitors 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

↑ Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet. 2000 Sep;26(1):19-20. PMID:10973241 doi:10.1038/79128
↑ Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van Maldergem L, Vanhoenacker F, Verbruggen L, Van Hul W. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet. 2000 Nov;26(3):273-5. PMID:11062463 doi:10.1038/81563
↑ Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem. 2003 Feb 28;278(9):7718-24. Epub 2002 Dec 18. PMID:12493741 doi:10.1074/jbc.M208857200
↑ McGowan NW, MacPherson H, Janssens K, Van Hul W, Frith JC, Fraser WD, Ralston SH, Helfrich MH. A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro. J Clin Endocrinol Metab. 2003 Jul;88(7):3321-6. PMID:12843182
↑ Kinoshita A, Fukumaki Y, Shirahama S, Miyahara A, Nishimura G, Haga N, Namba A, Ueda H, Hayashi H, Ikegawa S, Seidel J, Niikawa N, Yoshiura K. TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations. Am J Med Genet A. 2004 May 15;127A(1):104-7. PMID:15103729 doi:10.1002/ajmg.a.20671
↑ 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, Schürpf T, Carven GJ, Qatanani M, Fogel AI. An antibody that inhibits TGF-β1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis. Sci Signal. 2024 Jul 9;17(844):eadn6052. PMID:38980922 doi:10.1126/scisignal.adn6052

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OCA

[1] Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet. 2000 Sep;26(1):19-20. PMID:10973241 doi:10.1038/79128

[2] Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van Maldergem L, Vanhoenacker F, Verbruggen L, Van Hul W. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet. 2000 Nov;26(3):273-5. PMID:11062463 doi:10.1038/81563

[3] Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem. 2003 Feb 28;278(9):7718-24. Epub 2002 Dec 18. PMID:12493741 doi:10.1074/jbc.M208857200

[4] McGowan NW, MacPherson H, Janssens K, Van Hul W, Frith JC, Fraser WD, Ralston SH, Helfrich MH. A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro. J Clin Endocrinol Metab. 2003 Jul;88(7):3321-6. PMID:12843182

[5] Kinoshita A, Fukumaki Y, Shirahama S, Miyahara A, Nishimura G, Haga N, Namba A, Ueda H, Hayashi H, Ikegawa S, Seidel J, Niikawa N, Yoshiura K. TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations. Am J Med Genet A. 2004 May 15;127A(1):104-7. PMID:15103729 doi:10.1002/ajmg.a.20671

[6] 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, Schürpf T, Carven GJ, Qatanani M, Fogel AI. An antibody that inhibits TGF-β1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis. Sci Signal. 2024 Jul 9;17(844):eadn6052. PMID:38980922 doi:10.1126/scisignal.adn6052

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8udz

The Structure of LTBP-49247 Fab Bound to TGFbeta1 Small Latent Complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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