TY - JOUR
T1 - Structural basis for receptor selectivity and inverse agonism in S1P5 receptors
AU - Lyapina, Elizaveta
AU - Marin, Egor
AU - Gusach, Anastasiia
AU - Orekhov, Philipp
AU - Gerasimov, Andrey
AU - Luginina, Aleksandra
AU - Vakhrameev, Daniil
AU - Ergasheva, Margarita
AU - Kovaleva, Margarita
AU - Khusainov, Georgii
AU - Khorn, Polina
AU - Shevtsov, Mikhail
AU - Kovalev, Kirill
AU - Bukhdruker, Sergey
AU - Okhrimenko, Ivan
AU - Popov, Petr
AU - Hu, Hao
AU - Weierstall, Uwe
AU - Liu, Wei
AU - Cho, Yunje
AU - Gushchin, Ivan
AU - Rogachev, Andrey
AU - Bourenkov, Gleb
AU - Park, Sehan
AU - Park, Gisu
AU - Hyun, Hyo Jung
AU - Park, Jaehyun
AU - Gordeliy, Valentin
AU - Borshchevskiy, Valentin
AU - Mishin, Alexey
AU - Cherezov, Vadim
N1 - Funding Information:
We thank S. Ustinova, A. Podzorov, A. Awawdeh, P. Utrobin, and Yu. Semenov for technical assistance, T. Maruyama for providing ONO-5430608. We acknowledge the Paul Scherrer Institut, Villigen, Switzerland for the provision of synchrotron radiation beamtime at beamline PX1 of the SLS and would like to thank Dr. V. Olieric for assistance. The authors are grateful to the staff of the accelerator and beamline departments at PAL-XFEL for their technical support. The XFEL experiments were performed at the NCI PAL-XFEL experimental station under proposal No. 2019-2nd-NCI-012. Protein production and crystallization were supported by the Ministry of Science and Higher Education of the Russian Federation agreement 075-00337-20-03, project FSMG-2020-0003 (V.B., A.M., E.L., A.Gu., M.S., A.L.). XFEL and synchrotron data collection and treatment were supported by the Russian Ministry of Science and Higher Education grant No. 075-15-2021-1354 (V.B., A.M., E.M., E.L., A.R.). SFX data collection strategy was developed with the support from the Russian Foundation for Basic Research (RFBR) project 18-02-40020 (V.B., A.M., E.M.). Functional assays were developed and implemented with the support of the Russian Science Foundation project 22-74-10036 (A.M., A.L., E.L.). Molecular docking simulations were supported by the Russian Science Foundation project 22-24-00454 (E.M., M.K.). J.P. and Y.C. were supported by the National Research Foundation of Korea (grant No. NRF-2017M3A9F6029736). U.W. is supported by the National Science Foundation (NSF) BioXFEL Science and Technology Center award 1231306. W.L. is supported by the Advancing Healthier Wisconsin Endowment (AHW) fund. The authors are grateful to the Global Science Experimental Data Hub Center (GSDC) for data computing and the Korea Research Environment Open NETwork (KREONET) for network service provided by the Korea Institute of Science and Technology Information (KISTI) and the Data Processing Center of Moscow Institute of Physics and Technology for high-performance data computing infrastructure and technical support.
Funding Information:
We thank S. Ustinova, A. Podzorov, A. Awawdeh, P. Utrobin, and Yu. Semenov for technical assistance, T. Maruyama for providing ONO-5430608. We acknowledge the Paul Scherrer Institut, Villigen, Switzerland for the provision of synchrotron radiation beamtime at beamline PX1 of the SLS and would like to thank Dr. V. Olieric for assistance. The authors are grateful to the staff of the accelerator and beamline departments at PAL-XFEL for their technical support. The XFEL experiments were performed at the NCI PAL-XFEL experimental station under proposal No. 2019-2nd-NCI-012. Protein production and crystallization were supported by the Ministry of Science and Higher Education of the Russian Federation agreement 075-00337-20-03, project FSMG-2020-0003 (V.B., A.M., E.L., A.Gu., M.S., A.L.). XFEL and synchrotron data collection and treatment were supported by the Russian Ministry of Science and Higher Education grant No. 075-15-2021-1354 (V.B., A.M., E.M., E.L., A.R.). SFX data collection strategy was developed with the support from the Russian Foundation for Basic Research (RFBR) project 18-02-40020 (V.B., A.M., E.M.). Functional assays were developed and implemented with the support of the Russian Science Foundation project 22-74-10036 (A.M., A.L., E.L.). Molecular docking simulations were supported by the Russian Science Foundation project 22-24-00454 (E.M., M.K.). J.P. and Y.C. were supported by the National Research Foundation of Korea (grant No. NRF-2017M3A9F6029736). U.W. is supported by the National Science Foundation (NSF) BioXFEL Science and Technology Center award 1231306. W.L. is supported by the Advancing Healthier Wisconsin Endowment (AHW) fund. The authors are grateful to the Global Science Experimental Data Hub Center (GSDC) for data computing and the Korea Research Environment Open NETwork (KREONET) for network service provided by the Korea Institute of Science and Technology Information (KISTI) and the Data Processing Center of Moscow Institute of Physics and Technology for high-performance data computing infrastructure and technical support.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PRs) - S1P1-5. S1P5 is predominantly expressed in nervous and immune systems, regulating the egress of natural killer cells from lymph nodes and playing a role in immune and neurodegenerative disorders, as well as carcinogenesis. Several S1PR therapeutic drugs have been developed to treat these diseases; however, they lack receptor subtype selectivity, which leads to side effects. In this article, we describe a 2.2 Å resolution room temperature crystal structure of the human S1P5 receptor in complex with a selective inverse agonist determined by serial femtosecond crystallography (SFX) at the Pohang Accelerator Laboratory X-Ray Free Electron Laser (PAL-XFEL) and analyze its structure-activity relationship data. The structure demonstrates a unique ligand-binding mode, involving an allosteric sub-pocket, which clarifies the receptor subtype selectivity and provides a template for structure-based drug design. Together with previously published S1PR structures in complex with antagonists and agonists, our structure with S1P5-inverse agonist sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR family.
AB - The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PRs) - S1P1-5. S1P5 is predominantly expressed in nervous and immune systems, regulating the egress of natural killer cells from lymph nodes and playing a role in immune and neurodegenerative disorders, as well as carcinogenesis. Several S1PR therapeutic drugs have been developed to treat these diseases; however, they lack receptor subtype selectivity, which leads to side effects. In this article, we describe a 2.2 Å resolution room temperature crystal structure of the human S1P5 receptor in complex with a selective inverse agonist determined by serial femtosecond crystallography (SFX) at the Pohang Accelerator Laboratory X-Ray Free Electron Laser (PAL-XFEL) and analyze its structure-activity relationship data. The structure demonstrates a unique ligand-binding mode, involving an allosteric sub-pocket, which clarifies the receptor subtype selectivity and provides a template for structure-based drug design. Together with previously published S1PR structures in complex with antagonists and agonists, our structure with S1P5-inverse agonist sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR family.
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U2 - 10.1038/s41467-022-32447-1
DO - 10.1038/s41467-022-32447-1
M3 - Article
C2 - 35961984
AN - SCOPUS:85135832975
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4736
ER -