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Projeto de investigação
A multidisciplinary training network for the bioinspired development of glycomimetics tuning the Siglec-Sialoglycan axis
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Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b
Publication . Lenza, Maria Pia; Egia-Mendikute, Leire; Antoñana-Vildosola, Asier; Soares, Cátia O.; Coelho, Helena; Corzana, Francisco; Bosch, Alexandre; Manisha, Prodhi; Quintana, Jon Imanol; Oyenarte, Iker; Unione, Luca; Moure, María Jesús; Azkargorta, Mikel; Atxabal, Unai; Sobczak, Klaudia; Elortza, Felix; Sutherland, James D.; Barrio, Rosa; Marcelo, Filipa; Jiménez-Barbero, Jesús; Palazon, Asis; Ereño-Orbea, June; DQ - Departamento de Química; UCIBIO - Applied Molecular Biosciences Unit; Nature Portfolio
Sialic acid-binding Ig-like lectin 15 (Siglec-15) is an immune modulator and emerging cancer immunotherapy target. However, limited understanding of its structure and mechanism of action restrains the development of drug candidates that unleash its full therapeutic potential. In this study, we elucidate the crystal structure of Siglec-15 and its binding epitope via co-crystallization with an anti-Siglec-15 blocking antibody. Using saturation transfer-difference nuclear magnetic resonance (STD-NMR) spectroscopy and molecular dynamics simulations, we reveal Siglec-15 binding mode to α(2,3)- and α(2,6)-linked sialic acids and the cancer-associated sialyl-Tn (STn) glycoform. We demonstrate that binding of Siglec-15 to T cells, which lack STn expression, depends on the presence of α(2,3)- and α(2,6)-linked sialoglycans. Furthermore, we identify the leukocyte integrin CD11b as a Siglec-15 binding partner on human T cells. Collectively, our findings provide an integrated understanding of the structural features of Siglec-15 and emphasize glycosylation as a crucial factor in controlling T cell responses.
Unraveling Molecular Recognition of Glycan Ligands by Siglec-9 via NMR Spectroscopy and Molecular Dynamics Modeling
Publication . Atxabal, Unai; Nycholat, Corwin; Pröpster, Johannes M.; Fernández , Andrea; Oyenarte, Iker; Lenza, Maria Pia; Franconetti, Antonio; Soares, Cátia O.; Coelho, Helena; Marcelo, Filipa; Schubert, Mario; Paulson, James C.; Jiménez-Barbero, Jesús; Ereño-Orbea, June; DQ - Departamento de Química; UCIBIO - Applied Molecular Biosciences Unit; ACS - American Chemical Society
Human sialic-acid-binding immunoglobulin-like lectin-9 (Siglec-9) is a glycoimmune checkpoint receptor expressed on several immune cells. Binding of Siglec-9 to sialic acid containing glycans (sialoglycans) is well documented to modulate its functions as an inhibitory receptor. Here, we first assigned the amino acid backbone of the Siglec-9 V-set domain (Siglec-9d1), using well-established triple resonance three-dimensional nuclear magnetic resonance (NMR) methods. Then, we combined solution NMR and molecular dynamic simulation methods to decipher the molecular details of the interaction of Siglec-9 with the natural ligands α2,3 and α2,6 sialyl lactosamines (SLN), sialyl Lewis X (sLeX), and 6-O sulfated sLeX and with two synthetically modified sialoglycans that bind with high affinity. As expected, Neu5Ac is accommodated between the F and G β-strands at the canonical sialic acid binding site. Addition of a heteroaromatic scaffold 9N-5-(2-methylthiazol-4-yl)thiophene sulfonamide (MTTS) at the C9 position of Neu5Ac generates new interactions with the hydrophobic residues located at the G-G′ loop and the N-terminal region of Siglec-9. Similarly, the addition of the aromatic substituent (5-N-(1-benzhydryl-1H-1,2,3-triazol-4-yl)methyl (BTC)) at the C5 position of Neu5Ac stabilizes the conformation of the long and flexible B′-C loop present in Siglec-9. These results expose the underlying mechanism responsible for the enhanced affinity and specificity for Siglec-9 for these two modified sialoglycans and sheds light on the rational design of the next generation of modified sialoglycans targeting Siglec-9.
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Entidade financiadora
European Commission
Programa de financiamento
H2020
Número da atribuição
956758