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

J 2023

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

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

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

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

Abstract

V originále

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.

Citovat

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.

@article{2309598,
   author = {Sladek, Vladimir and Šmak, Pavel and Tvaroska, Igor},
   article_location = {WASHINGTON},
   article_number = {17},
   doi = {http://dx.doi.org/10.1021/acs.jcim.3c00704},
   keywords = {Selectins; Critical Residue Interactions},
   language = {eng},
   issn = {1549-9596},
   journal = {Journal of Chemical Information and Modeling},
   title = {How E-, L-, and P-Selectins Bind to sLe(x) and PSGL-1: A Quantification of Critical Residue Interactions},
   url = {https://pubs.acs.org/doi/10.1021/acs.jcim.3c00704},
   volume = {63},
   year = {2023}
}

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  -

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. \textit{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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