Unraveling Molecular Recognition of Glycan Ligands by Siglec-9 via NMR Spectroscopy and Molecular Dynamics Modeling
Atxabal, Unai (Centro de investigación cooperativa en Biociencias (CIC bioGUNE))
Nycholat, Corwin (The Scripps Research Institute)
Pröpster, Johannes M. (ETH Zurich)
Fernández, Andrea (Centro de investigación cooperativa en Biociencias (CIC bioGUNE))
Oyenarte, Iker (Centro de investigación cooperativa en Biociencias (CIC bioGUNE))
Lenza, Maria Pia (Centro de investigación cooperativa en Biociencias (CIC bioGUNE))
Franconetti, Antonio (Centro de investigación cooperativa en Biociencias (CIC bioGUNE))
Soares, Cátia O. (Universidade Nova de Lisboa)
Coelho, Helena (Universidade Nova de Lisboa)
Marcelo, Filipa (Universidade Nova de Lisboa)
Schubert, Mario (University of Salzburg)
Paulson, James C. (The Scripps Research Institute)
Jiménez Barbero, Jesús (Centro de investigación cooperativa en Biociencias (CIC bioGUNE))
Ereño-Orbea, June (Centro de investigación cooperativa en Biociencias (CIC bioGUNE))

Data:	2024
Descripció:	14 pàg.
Resum:	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.
Ajuts:	European Commission 956758 European Commission 788143 European Commission 860325 Agencia Estatal de Investigación PID2019-107770RA-I00 Ministerio de Ciencia e Innovación CEX2021-001136-S
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	ACS chemical biology, Vol. 19, Num. 2 (February 2024) , p. 483-496, ISSN 1554-8929

DOI: 10.1021/acschembio.3c00664
PMID: 38321945

14 p, 6.5 MB

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