How E-, L-, and P-Selectins Bind to sLe(x) and PSGL-1: A
Quantification of Critical Residue Interactions

SLADEK, Vladimir, Pavel ŠMAK and Igor TVAROSKA. How E-, L-, and P-Selectins Bind to sLe(x) and PSGL-1: A Quantification of Critical Residue Interactions. Journal of Chemical Information and Modeling. WASHINGTON: AMER CHEMICAL SOC, 2023, vol. 63, No 17, p. 5604-5618. ISSN 1549-9596. Available from: https://dx.doi.org/10.1021/acs.jcim.3c00704.

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TY  - JOUR
ID  - 2309598
AU  - Sladek, Vladimir - Šmak, Pavel - Tvaroska, Igor
PY  - 2023
TI  - How E-, L-, and P-Selectins Bind to sLe(x) and PSGL-1: A Quantification of Critical Residue Interactions
JF  - Journal of Chemical Information and Modeling
VL  - 63
IS  - 17
SP  - 5604-5618
EP  - 5604-5618
PB  - AMER CHEMICAL SOC
SN  - 15499596
KW  - Selectins
KW  - Critical Residue Interactions
UR  - https://pubs.acs.org/doi/10.1021/acs.jcim.3c00704
N2  - Selectins and their ability to interact with specific ligands are a cornerstone in cell communication. Over the last three decades, a considerable wealth of experimental and molecular modeling insights into their structure and modus operandi were gathered. Nonetheless, explaining the role of individual selectin residues on a quantitative level remained elusive, despite its importance in understanding the structure-function relationship in these molecules and designing their inhibitors. This work explores essential interactions of selectin-ligand binding, employing a multiscale approach that combines molecular dynamics, quantumchemical calculations, and residue interaction network models. Such an approach successfully reproduces most of the experimental findings. It proves to be helpful, with the potential for becoming an established tool for quantitative predictions of residue contribution to the binding of biomolecular complexes. The results empower us to quantify the importance of particular residues and functional groups in the protein-ligand interface and to pinpoint differences in molecular recognition by the three selectins. We show that mutations in the E-, L-, and P-selectins, e.g., different residues in positions 46, 85, 97, and 107, present a crucial difference in how the ligand is engaged. We assess the role of sulfation of tyrosine residues in PSGL-1 and suggest that TyrSO3- in position 51 interacting with Arg85 in P-selectin is a significant factor in the increased affinity of P-selectin to PSGL-1 compared to E- and L-selectins. We propose an original pharmacophore targeting five essential PSGL-binding sites based on the analysis of the selectin center dot center dot center dot PSGL-1 interactions.
ER  -

Basic information
Original name	How E-, L-, and P-Selectins Bind to sLe(x) and PSGL-1: A Quantification of Critical Residue Interactions
Authors	SLADEK, Vladimir (guarantor), Pavel ŠMAK (203 Czech Republic, belonging to the institution) and Igor TVAROSKA.
Edition	Journal of Chemical Information and Modeling, WASHINGTON, AMER CHEMICAL SOC, 2023, 1549-9596.

Other information
Original language	English
Type of outcome	Article in a journal
Field of Study	10608 Biochemistry and molecular biology
Country of publisher	United States of America
Confidentiality degree	is not subject to a state or trade secret
WWW	URL
Impact factor	Impact factor: 5.600 in 2022
RIV identification code	RIV/00216224:14110/23:00131650
Organization unit	Faculty of Medicine
Doi	http://dx.doi.org/10.1021/acs.jcim.3c00704
UT WoS	001032527500001
Keywords in English	Selectins; Critical Residue Interactions
Tags	14110512, rivok
Tags	International impact, Reviewed
Changed by	Changed by: Mgr. Tereza Miškechová, učo 341652. Changed: 16/10/2023 07:49.

Abstract

Selectins and their ability to interact with specific ligands are a cornerstone in cell communication. Over the last three decades, a considerable wealth of experimental and molecular modeling insights into their structure and modus operandi were gathered. Nonetheless, explaining the role of individual selectin residues on a quantitative level remained elusive, despite its importance in understanding the structure-function relationship in these molecules and designing their inhibitors. This work explores essential interactions of selectin-ligand binding, employing a multiscale approach that combines molecular dynamics, quantumchemical calculations, and residue interaction network models. Such an approach successfully reproduces most of the experimental findings. It proves to be helpful, with the potential for becoming an established tool for quantitative predictions of residue contribution to the binding of biomolecular complexes. The results empower us to quantify the importance of particular residues and functional groups in the protein-ligand interface and to pinpoint differences in molecular recognition by the three selectins. We show that mutations in the E-, L-, and P-selectins, e.g., different residues in positions 46, 85, 97, and 107, present a crucial difference in how the ligand is engaged. We assess the role of sulfation of tyrosine residues in PSGL-1 and suggest that TyrSO3- in position 51 interacting with Arg85 in P-selectin is a significant factor in the increased affinity of P-selectin to PSGL-1 compared to E- and L-selectins. We propose an original pharmacophore targeting five essential PSGL-binding sites based on the analysis of the selectin center dot center dot center dot PSGL-1 interactions.

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How E-, L-, and P-Selectins Bind to sLe(x) and PSGL-1: A Quantification of Critical Residue ...

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