Elucidation of Mechanism for Ligand Efficacy at Leukotriene B4Receptor 2 (BLT2)

Minsup Kim; Jun Dong Wei; Dipesh S. Harmalkar; Ja Il Goo; Kyeong Lee; Yongseok Choi; Jae Hong Kim; Art E. Cho

doi:10.1021/acsmedchemlett.0c00065

Elucidation of Mechanism for Ligand Efficacy at Leukotriene B₄Receptor 2 (BLT2)

Minsup Kim, Jun Dong Wei, Dipesh S. Harmalkar, Ja Il Goo, Kyeong Lee, Yongseok Choi, Jae Hong Kim, Art E. Cho

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

G protein-coupled receptors (GPCRs) have always been important drug targets in the pharmaceutical industry. One major question for the current GPCR drug discovery is how drugs have distinct efficacies at the same GPCR target. Related to this question, we studied how different ligands can have disparate efficacies at Leukotriene B4 receptor (BLT2). By using molecular modeling studies, we predicted that Tyr2716.51 located at TM6 of BLT2 performs as a key trigger for its activation and verified the prediction by site-directed mutagenesis, chemotactic motility studies, which included a chemical derivative of agonist CAY10583. We further identified Asn2756.55 located at TM6 as a weak activation trigger in BLT2 and performed double mutation studies to confirm our computational results. Our results provide strong evidence for the exact mechanism of ligand efficacy at BLT2.

Original language	English
Pages (from-to)	1529-1534
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	8
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00065
Publication status	Published - 2020 Aug 13

Bibliographical note

Funding Information:
This work was partly supported by National Research Foundation of Korea (NRF) [2020R1A2C1011059, 2020R1A2B5B01002046, 2019R1F1A1059339, 2018R1D1A1B07046939, 2017M3A9D8063317, and 2018R1A5A2023127], Technology Development Program of MSS [S2832693], and Korea University Grant [K1903051].

Publisher Copyright:
Copyright © 2020 American Chemical Society.

Keywords

Leukotriene Breceptor 2
chemical study
ligand efficacy
molecular modeling
mutagenesis study

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1021/acsmedchemlett.0c00065

Cite this

@article{52b91fdec1dd4ac3900b8e0f25c3b997,

title = "Elucidation of Mechanism for Ligand Efficacy at Leukotriene B4Receptor 2 (BLT2)",

abstract = "G protein-coupled receptors (GPCRs) have always been important drug targets in the pharmaceutical industry. One major question for the current GPCR drug discovery is how drugs have distinct efficacies at the same GPCR target. Related to this question, we studied how different ligands can have disparate efficacies at Leukotriene B4 receptor (BLT2). By using molecular modeling studies, we predicted that Tyr2716.51 located at TM6 of BLT2 performs as a key trigger for its activation and verified the prediction by site-directed mutagenesis, chemotactic motility studies, which included a chemical derivative of agonist CAY10583. We further identified Asn2756.55 located at TM6 as a weak activation trigger in BLT2 and performed double mutation studies to confirm our computational results. Our results provide strong evidence for the exact mechanism of ligand efficacy at BLT2.",

keywords = "Leukotriene Breceptor 2, chemical study, ligand efficacy, molecular modeling, mutagenesis study",

author = "Minsup Kim and Wei, {Jun Dong} and Harmalkar, {Dipesh S.} and Goo, {Ja Il} and Kyeong Lee and Yongseok Choi and Kim, {Jae Hong} and Cho, {Art E.}",

note = "Funding Information: This work was partly supported by National Research Foundation of Korea (NRF) [2020R1A2C1011059, 2020R1A2B5B01002046, 2019R1F1A1059339, 2018R1D1A1B07046939, 2017M3A9D8063317, and 2018R1A5A2023127], Technology Development Program of MSS [S2832693], and Korea University Grant [K1903051]. Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

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AU - Goo, Ja Il

AU - Lee, Kyeong

AU - Choi, Yongseok

AU - Kim, Jae Hong

AU - Cho, Art E.

N1 - Funding Information: This work was partly supported by National Research Foundation of Korea (NRF) [2020R1A2C1011059, 2020R1A2B5B01002046, 2019R1F1A1059339, 2018R1D1A1B07046939, 2017M3A9D8063317, and 2018R1A5A2023127], Technology Development Program of MSS [S2832693], and Korea University Grant [K1903051]. Publisher Copyright: Copyright © 2020 American Chemical Society.

PY - 2020/8/13

Y1 - 2020/8/13

N2 - G protein-coupled receptors (GPCRs) have always been important drug targets in the pharmaceutical industry. One major question for the current GPCR drug discovery is how drugs have distinct efficacies at the same GPCR target. Related to this question, we studied how different ligands can have disparate efficacies at Leukotriene B4 receptor (BLT2). By using molecular modeling studies, we predicted that Tyr2716.51 located at TM6 of BLT2 performs as a key trigger for its activation and verified the prediction by site-directed mutagenesis, chemotactic motility studies, which included a chemical derivative of agonist CAY10583. We further identified Asn2756.55 located at TM6 as a weak activation trigger in BLT2 and performed double mutation studies to confirm our computational results. Our results provide strong evidence for the exact mechanism of ligand efficacy at BLT2.

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