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Structure and Ligand Binding Properties at The TURUN YLIOPISTON JULKAISUJA ANNALES UNIVERSITATIS TURKUENSIS TURUN YLIOPISTON JULKAISUJA ANNALES UNIVERSITATIS TURKUENSIS SARJA - SER. D OSA - TOM. 962 SARJA - SER. D OSA - TOM. XXX MEDICA - ODONTOLOGICA MEDICA - ODONTOLOGICA 2-ADRENOCEPTORS: STRUCTURE α2-ADRENOCEPTORS: STRUCTURE AND LIGAND BINDING PROPERTIES AND LIGAND BINDING PROPERTIES AT THE MOLECULAR LEVEL AT THE MOLECULAR LEVEL by by Jonne M.M. Laurila Jonne M.M. Laurila TURUN YLIOPISTO Turku 2011 TURUN YLIOPISTO UNIVERSITY OF TURKU Turku 2011 From the Institute of Biomedicine, From the Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics Department of Pharmacology, Drug Development and Therapeutics University of Turku University of Turku Turku, Finland Turku, Finland Supervised by Supervised by Professor Mika Scheinin, MD, PhD Professor Mika Scheinin, MD, PhD Department of Pharmacology, Drug Development and Therapeutics Department of Pharmacology, Drug Development and Therapeutics University of Turku University of Turku Turku, Finland Turku, Finland Reviewed by Reviewed by Docent Jarmo T. Laitinen, PhD Docent Jarmo T. Laitinen, PhD Institute of Biomedicine/Physiology Institute of Biomedicine/Physiology University of Eastern Finland University of Eastern Finland Kuopio, Finland Kuopio, Finland and and Docent Ulla Petäjä-Repo, PhD Docent Ulla Petäjä-Repo, PhD Institute of Biomedicine/Department of Anatomy and Cell Biology Institute of Biomedicine/Department of Anatomy and Cell Biology University of Oulu University of Oulu Oulu, Finland Oulu, Finland Dissertation opponent Dissertation opponent Professor Heikki Ruskoaho, MD, PhD Professor Heikki Ruskoaho, MD, PhD Institute of Biomedicine/Department of Pharmacology and Toxicology Institute of Biomedicine/Department of Pharmacology and Toxicology University of Oulu University of Oulu Oulu, Finland Oulu, Finland ISBN 978-951-29-4606-8 (PRINT) ISBN 978-951-29-4606-8 (PRINT) ISBN 978-951-29-4607-5 (PDF) ISBN 978-951-29-4607-5 (PDF) ISSN 0355-9483 ISSN 0355-9483 Painosalama Oy – Turku, Finland 2011 Painosalama Oy – Turku, Finland 2011 In memory of my father In memory of my father Tapani Laurila (1939-2006) Tapani Laurila (1939-2006) Jonne M.M. Laurila Jonne M.M. Laurila 2-Adrenoceptors: structure and ligand binding properties at the molecular level 2-Adrenoceptors: structure and ligand binding properties at the molecular level Institute of Biomedicine, Department of Pharmacology, Drug Development and Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku; and Drug Discovery Graduate School, Turku, Therapeutics, University of Turku; and Drug Discovery Graduate School, Turku, Finland Finland Annales Universitatis Turkuensis, Painosalama Oy, Turku, Finland 2011 Annales Universitatis Turkuensis, Painosalama Oy, Turku, Finland 2011 ABSTRACT ABSTRACT The mouse is the most frequently used animal model in biomedical research, but the The mouse is the most frequently used animal model in biomedical research, but the use of zebrafish as a model organism to mimic human diseases is on the increase. use of zebrafish as a model organism to mimic human diseases is on the increase. Therefore it is considered important to understand their pharmacological differences Therefore it is considered important to understand their pharmacological differences from humans also at the molecular level. from humans also at the molecular level. The zebrafish 2-adrenoceptors were expressed in mammalian cells and the binding The zebrafish 2-adrenoceptors were expressed in mammalian cells and the binding affinities of 20 diverse ligands were determined and compared to the corresponding affinities of 20 diverse ligands were determined and compared to the corresponding human receptors. The pharmacological properties of the human and zebrafish 2- human receptors. The pharmacological properties of the human and zebrafish 2- adrenoceptors were found to be quite well conserved. adrenoceptors were found to be quite well conserved. Receptor models based on the crystal structures of bovine rhodopsin and the human Receptor models based on the crystal structures of bovine rhodopsin and the human 2-adrenoceptor revealed that most structural differences between the paralogous and 2-adrenoceptor revealed that most structural differences between the paralogous and orthologous 2-adrenoceptors were located within the second extracellular loop (XL2). orthologous 2-adrenoceptors were located within the second extracellular loop (XL2). Reciprocal mutations were generated in the mouse and human 2A-adrenoceptors. Reciprocal mutations were generated in the mouse and human 2A-adrenoceptors. Ligand binding experiments revealed that substitutions in XL2 reversed the binding Ligand binding experiments revealed that substitutions in XL2 reversed the binding profiles of the human and mouse 2A-adrenoceptors for yohimbine, rauwolscine and profiles of the human and mouse 2A-adrenoceptors for yohimbine, rauwolscine and RS-79948-197, evidence for a role for XL2 in the determination of species-specific RS-79948-197, evidence for a role for XL2 in the determination of species-specific ligand binding. ligand binding. Previous mutagenesis studies had not been able to explain the subtype preference of Previous mutagenesis studies had not been able to explain the subtype preference of several large 2-adrenoceptor antagonists. We prepared chimaeric 2-adrenoceptors several large 2-adrenoceptor antagonists. We prepared chimaeric 2-adrenoceptors where the first transmembrane (TM1) domain was exchanged between the three human where the first transmembrane (TM1) domain was exchanged between the three human 2-adrenoceptor subtypes. The binding affinities of spiperone, spiroxatrine and 2-adrenoceptor subtypes. The binding affinities of spiperone, spiroxatrine and chlorpromazine were observed to be significantly improved by TM1 substitutions of chlorpromazine were observed to be significantly improved by TM1 substitutions of the 2A-adrenoceptor. Docking simulations indicated that indirect effects, such as the 2A-adrenoceptor. Docking simulations indicated that indirect effects, such as allosteric modulation, are more likely to be involved in this phenomenon rather than allosteric modulation, are more likely to be involved in this phenomenon rather than specific side-chain interactions between ligands and receptors. specific side-chain interactions between ligands and receptors. Key words: 2-adrenoceptor, GPCR, ligand binding, XL2, receptor models Key words: 2-adrenoceptor, GPCR, ligand binding, XL2, receptor models Jonne M.M. Laurila Jonne M.M. Laurila 2-Adrenoseptorit: rakenne ja lääkeaineiden sitoutumisominaisuudet 2-Adrenoseptorit: rakenne ja lääkeaineiden sitoutumisominaisuudet molekyylitasolla molekyylitasolla Biolääketieteen laitos, Farmakologia, lääkekehitys ja lääkehoito, Turun yliopisto; Biolääketieteen laitos, Farmakologia, lääkekehitys ja lääkehoito, Turun yliopisto; Lääkekehityksen tutkijakoulu (DDGS), Turku Lääkekehityksen tutkijakoulu (DDGS), Turku Annales Universitatis Turkuensis, Painosalama Oy, Turku 2011 Annales Universitatis Turkuensis, Painosalama Oy, Turku 2011 TIIVISTELMÄ TIIVISTELMÄ Biolääketieteen tutkimuksessa hiiri on yleisimmin käytetty koe-eläin, mutta Biolääketieteen tutkimuksessa hiiri on yleisimmin käytetty koe-eläin, mutta seeprakalan käyttö ihmisen sairauksien mallinnuksessa on lisääntymässä. Siksi on seeprakalan käyttö ihmisen sairauksien mallinnuksessa on lisääntymässä. Siksi on tärkeää tutkia ja ymmärtää näiden eläinten ja ihmisten farmakologisten ominaisuuksien tärkeää tutkia ja ymmärtää näiden eläinten ja ihmisten farmakologisten ominaisuuksien eroavaisuuksia myös molekyylitasolla. eroavaisuuksia myös molekyylitasolla. Seeprakalan 2-adrenoseptoreja tuotettiin nisäkässoluissa ja verrattiin 20 erilaisen Seeprakalan 2-adrenoseptoreja tuotettiin nisäkässoluissa ja verrattiin 20 erilaisen lääkeyhdisteen sitoutumista niihin ja ihmisen vastaaviin reseptoreihin. Ihmisen ja lääkeyhdisteen sitoutumista niihin ja ihmisen vastaaviin reseptoreihin. Ihmisen ja seeprakalan 2-adrenoseptorien farmakologiset ominaisuudet todettiin hyvin saman- seeprakalan 2-adrenoseptorien farmakologiset ominaisuudet todettiin hyvin saman- laisiksi. laisiksi. Naudan rodopsiinin ja ihmisen 2-adrenoseptorin kiderakenteisiin perustuvat 2- Naudan rodopsiinin ja ihmisen 2-adrenoseptorin kiderakenteisiin perustuvat 2- reseptorien rakennemallit osoittivat, että suurimmat rakenne-erot sekä reseptoriala- reseptorien rakennemallit osoittivat, että suurimmat rakenne-erot sekä reseptoriala- tyyppien että eri eläinlajien reseptorien välillä löytyvät reseptorien toisesta solun- tyyppien että eri eläinlajien reseptorien välillä löytyvät reseptorien toisesta solun- ulkoisesta silmukkarakenteesta (XL2). Erilaiset aminohapot vaihdettiin hiiren ja ulkoisesta silmukkarakenteesta (XL2). Erilaiset aminohapot vaihdettiin hiiren ja ihmisen 2A-adrenoseptorien välillä toistensa kaltaisiksi. Näillä muokatuilla resepto- ihmisen 2A-adrenoseptorien välillä toistensa kaltaisiksi. Näillä muokatuilla resepto- reilla tehdyt sitoutumiskokeet osoittivat kolmen testatun lääkeaineen, johimbiinin, reilla tehdyt sitoutumiskokeet osoittivat kolmen testatun lääkeaineen, johimbiinin, rauwolskiinin ja RS-79948-197:n, sitoutumishanakkuuden muuttuvan vastaavasti. rauwolskiinin ja RS-79948-197:n, sitoutumishanakkuuden muuttuvan vastaavasti. Tulos osoitti, että XL2:n rakenne osaltaan määrittää eläinlajille tyypillisen lääke- Tulos osoitti, että XL2:n rakenne
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