XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity

The human MT1 and MT2 melatonin receptors1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns3. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer3, and MT2 has also been implicated in type 2 diabetes4,5. Here we report X-ray free electron laser (XFEL) structures of the human MT2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon6 at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H2085.46A (superscripts represent the Ballesteros–Weinstein residue numbering nomenclature7) and N862.50D, obtained in complex with 2-PMT. Comparison of the structures of MT2 with a published structure8 of MT1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [3H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT1 and MT2, but in addition the MT2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT2. Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents. © 2019, The Author(s), under exclusive licence to Springer Nature Limited

Observation Of Very High Energy Cosmic-ray Families In Emulsion Chambers At High Mountain Altitudes (i)

Characteristics of cosmic-ray hadronic interactions in the 1015 - 1017 eV range are studied by observing a total of 429 cosmic-ray families of visible energy greater than 100 TeV found in emulsion chamber experiments at high mountain altitudes, Chacaltaya (5200 m above sea level) and the Pamirs (4300 m above sea level). Extensive comparisons were made with simulated families based on models so far proposed, concentrating on the relation between the observed family flux and the behaviour of high-energy showers in the families, hadronic and electromagnetic components. It is concluded that there must be global change in characteristics of hadronic interactions at around 1016 eV deviating from thise known in the accelerator energy range, specially in the forwardmost angular region of the collision. A detailed study of a new shower phenomenon of small-pT particle emissions, pT being of the order of 10 MeV/c, is carried out and its relation to the origin of huge "halo" phenomena associated with extremely high energy families is discussed as one of the possibilities. General characteristics of such super-families are surveyed. © 1992.3702365431Borisov, (1981) Nucl. Phys., 191 BBaybrina, (1984) Trudy FIAN 154, p. 1. , [in Russian], Nauka, MoscowLattes, Hadronic interactions of high energy cosmic-ray observed by emulsion chambers (1980) Physics Reports, 65, p. 151Hasegawa, ICR-Report-151-87-5 (1987) presented at FNAL CDF Seminar, , Inst. for Cosmic Ray Research, Univ. of TokyoCHACALTAYA Emulsion Chamber Experiment (1971) Progress of Theoretical Physics Supplement, 47, p. 1Yamashita, Ohsawa, Chinellato, (1984) Proc. 3rd Int. Symp. on Cosmic Rays and Particle Physics, p. 30. , Tokyo, 1984, Inst. for Cosmic Ray Research, Univ. of Tokyo(1984) Proc. 3rd Int. Symp. on Cosmic Rays and Particle Physics, p. 1. , Tokyo, 1984Baradzei, (1984) Proc. 3rd Int. Symp. on Cosmic Rays and Particle Physics, p. 136. , Tokyo, 1984Yamashita, (1985) J. Phys. Soc. Jpn., 54, p. 529Bolisov, (1984) Proc. 3rd Int. Symp. on Cosmic rays and Particle Physics, p. 248. , Tokyo, 1984, Inst. for Cosmic Ray Research, Univ. of TokyoTamada, Tomaszewski, (1988) Proc. 5th Int. Symp. on Very High Energy Cosmic-Ray Interactions, p. 324. , Lodz, 1988, Inst. for Cosmic Ray Research, Univ. of Tokyo, PolandHasegawa, (1989) ICR-Report-197-89-14, , Inst. for Cosmic Ray Research, Univ. of TokyoCHACALTAYA Emulsion Chamber Experiment (1971) Progress of Theoretical Physics Supplement, 47, p. 1Okamoto, Shibata, (1987) Nucl. Instrum. Methods, 257 A, p. 155Zhdanov, (1980) FIAN preprint no. 45, , Lebedev Physical Institute, MoscowSemba, Gross Features of Nuclear Interactions around 1015eV through Observation of Gamma Ray Families (1983) Progress of Theoretical Physics Supplement, 76, p. 111Nikolsky, (1975) Izv. Akad. Nauk. USSR Ser. Fis., 39, p. 1160Burner, Energy spectra of cosmic rays above 1 TeV per nucleon (1990) The Astrophysical Journal, 349, p. 25Takahashi, (1990) 6th Int. Symp. on Very High Energy Cosmic-ray Interactions, , Tarbes, FranceRen, (1988) Phys. Rev., 38 D, p. 1404Alner, The UA5 high energy simulation program (1987) Nuclear Physics B, 291 B, p. 445Bozzo, Measurement of the proton-antiproton total and elastic cross sections at the CERN SPS collider (1984) Physics Letters B, 147 B, p. 392Wrotniak, (1985) Proc. 19th Cosmic-Ray Conf. La Jolla, 1985, 6, p. 56. , NASA Conference Publication, Washington, D.CWrotniak, (1985) Proc. 19th Cosmic-Ray Conf. La Jolla, 1985, 6, p. 328. , NASA Conference Publication, Washington, D.CMukhamedshin, (1984) Trudy FIAN, 154, p. 142. , Nauka, Moscow, [in Russian]Dunaevsky, Pluta, Slavatinsky, (1988) Proc. 5th Int. Symp. on Very High Energy Cosmic-Ray Interactions, p. 143. , Lodz, 1988, Inst. of Physics, Univ. of Lodz, PolandKaidalov, Ter-Martirosyan, (1987) Proc. 20th Int. Cosmic-Ray Conf., Moscow, 1987, 5, p. 141. , Nauka, MoscowShabelsky, (1985) preprints LNPI-1113Shabelsky, (1986) preprints LNPI-1224, , Leningrad [in Russian]Hillas, (1979) Proc. 16th Int. Cosmic-Ray Conf., Kyoto, 6, p. 13. , Inst. for Cosmic Ray Research, Univ. of TokyoBorisov, (1987) Phys. Lett., 190 B, p. 226Hasegawa, Tamada, (1990) 6th Int. Symp. on Very High Energy Cosmic-Ray Interactions, , Tarbes, FranceSemba, Gross Features of Nuclear Interactions around 1015eV through Observation of Gamma Ray Families (1983) Progress of Theoretical Physics Supplement, p. 111Ren, (1988) Phys. Rev., 38 D, p. 1404Dynaevsky, Zimin, (1988) Proc. 5th Int. Symp. on Very High Energy Cosmic-Ray Interaction, p. 93. , Lodz, 1988, Inst. of Physics, Univ. of Lodz, PolandDynaevsky, (1990) Proc. 6th Int. Symp. on Very High Energy Cosmic-Ray Interactions, , Tarbes, France(1989) FIAN preprint no. 208, , Lebedev Physical Institute, Moscow(1990) Proc. 21st Int. Cosmic-Ray Conf., Adelaide, 8, p. 259. , Dept. Physics and Mathematical Physics, Univ. of Adelaide, AustraliaHasegawa, (1990) ICR-Report-216-90-9, , Inst. for Cosmic-Ray Research, Univ. of TokyoTamada, (1990) Proc. 21st Int. Cosmic-Ray Conf., Adelaide, 1990, 8. , Dept. Physics and Mathematical Physics, Univ. of Adelaide, AustraliaTamada, (1990) ICR-Report-216-90-9(1981) Proc. 17th Int. Cosmic-Ray Conf., Paris, 5, p. 291(1990) Proc. Int. Cosmic-Ray Conf., Adelaide, 1990, 8, p. 267. , Dept. Physics and Mathematical Physics, Univ. of Adelaide, Australia(1989) Inst. Nucl. Phys. 89-67/144, , preprint, Inst. Nucl. Phys., Moscow State UnivSmilnova, (1988) Proc. 5th Int. Sym. on Very High Energy Cosmic-Ray Interactions, p. 42. , Lodz, 1988, Inst. of Physics, Univ. of Lodz, PolandGoulianos, (1986) Proc. Workshop of Particle Simulation at High Energies, , University of Wisconsin, Madison, USAIvanenko, (1983) Proc. 18th Int. Cosmic-Ray Conf., Bangalore, 1983, 5, p. 274. , Tata Inst. Fundamental Research, Bombay, IndiaIvanenko, (1984) Proc. Int. Symp. on Cosmic-Rays and Particle Physics, p. 101. , Tokyo, 1984, Inst. for Cosmic Ray Research, Univ. of Tokyo(1988) 5th Int. Symp. on Very High Energy Cosmic-Ray Interactions, p. 180. , Lodz, 1988, Inst. of Physics, Univ. of Lodz, Poland(1990) Proc. 21st Int. Cosmic-Ray Conf., Adelaide, 1990, 8, p. 251. , Dept. Physics and Mathematical Physics, Univ. of Adelaide, Australia(1991) Izv. AN USSR No. 4, , to be publishedNikolsky, Shaulov, Cherdyntseva, (1990) FIAN preprint no. 140, , Lebedev Physical Institute, Moscow, [in Russian](1987) Proc. 20th Int. Cosmic-Ray Conf., Moscow, 1987, 5, p. 326. , Nauka, Mosco

Observation Of A High-energy Cosmic-ray Family Caused By A Centauro-type Nuclear Interaction In The Joint Emulsion Chamber Experiment At The Pamirs

An exotic cosmic-ray family event is observed in the large emulsion chamber exposed by the joint at the Pamirs (4360 m above sea level). The family is composed of 120γ-ray-induced showers and 37 hadron-induced showers with individual visible energy exceeding 1 TeV. The decisive feature of the event is the hadron dominance: ΣEγ, ΣE(γ) h, 〈Eγ, 〈E(γ) h〉, 〈Eγ·Rγ〉 and 〈E(γ)·Rh〉 being 298 TeV, 476 TeV, 2.5 TeV, 12.9 TeV, 28.6 GeV m and 173 GeV m, respectively. Most probably the event is due to a Centauro interaction, which occured in the atmosphere at ∼700 m above the chamber. The event will constitute the second beautiful candidate for a Centauro observed at the Pamirs. © 1987.1901-2226233Bayburina, (1981) Nucl. Phys. B, 191, p. 1Lattes, Fujimoto, Hasegawa, Hadronic interactions of high energy cosmic-ray observed by emulsion chambers (1980) Physics Reports, 65, p. 151(1984) Trudy FIAN, 154, p. 1Borisov, (1984) Proc. Intern. Symp. on Cosmic rays and particle physics, p. 3. , TokyoRen, (1985) 19th Intern. Cosmic ray Conf., 6, p. 317. , La JollaYamashita, (1985) 19th Intern. Cosmic ray Conf., 6, p. 364. , La JollaTamada, (1977) Nuovo Cimento, 41 B, p. 245T. Shibata et al., to be publishedHillas, (1979) 16th Intern. Cosmic ray Conf., 6, p. 13. , KyotoBattiston, Measurement of the proton-antiproton elastic and total cross section at a centre-of-mass energy of 540 GeV (1982) Physics Letters B, 117, p. 126UA5 Collab., G.J. Alner et al., preprint CERN-EP/85-62Taylor, (1976) Phys. Rev. D, 14, p. 1217Burnett, (1984) Proc. Intern. Symp. on Cosmic rays and particle physics, p. 468. , Toky

Nuclear Interactions Of Super High Energy Cosmic-rays Observed In Mountain Emulsion Chambers

Here we present a summary of joint discussions on the results of three mountain experiments with large-scale emulsion chambers, at Pamir, Mt. Fuji and Chacaltaya. Observations cover gamma quanta, hadrons and their clusters (called "families"). The following topics are covered, concerning the characteristics of nuclear interactions the energy region 1014-1016 eV: (i) rapid dissipation seen in atmospheric diffusion of high-energy cosmic-rays; (ii) multiplicity and Pt increase in produced pi-mesons in the fragmentation region; (iii) existence of large-Pt jets, (iv) extremely hadron-rich family of the Centauro type; (v) exotic phenomena in the extremely high energy region beyond 1016 eV. © 1981.1911125(1977) Acta Univ. Lodz ser. II, (60)(1973) 13th Int. Cosmic-ray Conf., 3, p. 2228(1975) 14th Int. Cosmic-Ray Conf., 7, p. 2365(1979) AIP Conf. Proc. no. 49, p. 334(1979) 16th Int. Cosmic-ray Conf., 6, p. 344(1979) 16th Int. Cosmic-ray Conf., 7, p. 6816th Int. Cosmic-ray Conf. (1979) 16th Int. Cosmic-ray Conf., 7, p. 284(1979) 16th Int. Cosmic-ray Conf., 7, p. 294(1979) 16th Int. Cosmic-ray Conf., 13, p. 87(1979) 16th Int. Cosmic-ray Conf., 13, p. 92(1979) 16th Int. Cosmic-ray Conf., 13, p. 98(1979) AIP Conf. Proc. no. 49, p. 94(1979) AIP Conf. Proc. no. 49, p. 145(1979) AIP Conf. Proc. no. 49, p. 317(1979) 16th Int. Cosmic-ray Conf., 6, p. 350(1979) 16th Int. Cosmic-ray Conf., 6, p. 356(1979) 16th Int. Cosmic-ray Conf., 6, p. 362Nikolsky, Proc. 9th Int. High-energy Symp. (1978) CSSR, 21. , ToborMiyake, (1978) Proc. 19th Int. Conf. on High-energy physics, p. 433Vernov, (1977) Physica, 3, p. 1601Khristiansen, (1978) JETP Lett., 28, p. 124(1973) 13th Int. Cosmic-ray Conf., 3, p. 2219Izv. Acad. Nauk USSR, ser Phys. (1974) Izv. Acad. Nauk USSR, ser Phys., 38, p. 918(1975) 14th Int. Cosmic-ray Conf., 7, p. 2365(1979) 16th Int. Cosmic-ray Conf., 7, p. 68Dunaevsky, Urysson, Emelyanov, Shorin, Tashimov, (1975) FIAN preprint no. 150Dunaevsky, Urysson, Emelyanov, Shorin, Tashinov, (1979) Acta Univ. Lodz ser. II, (60), p. 199Ivanenko, Kanevskya, Roganova, (1978) JETP Lett., 40, p. 704Ivanenko, Kanevsky, Roganova, (1979) 16th Int. Cosmic-ray Conf., 7, p. 101Ivanenko, Kanevsky, Roganova, (1979) 16th Int. Cosmic-ray Conf., 7, p. 198Wrotniak, (1977) Acta Univ. Lodz ser. II, (60), p. 165Krys, Tomaszevski, Wrotniak, (1979) 16th Int. Cosmic-ray Conf., 7, p. 182Krys, Tomaszevski, Wrotniak, (1979) 16th Int. Cosmic-ray Conf., 7, p. 186Fomin, Kempa, Khristiansen, Levina, Piotrowska, Wdowczyk, (1977) 15th Int. Cosmic-ray Conf., 7, p. 248Fomin, Kempa, Khristiansen, Levina, Piotrowska, Wdowczyk, (1979) 16th Int. Cosmic-ray Conf., 13, p. 82Azimov, Mullazhanov, Yuldashbayev, (1979) 16th Int. Cosmic-ray Conf., 7, p. 262Azimov, Mullazhanov, Yuldashbayev, (1977) Acta Univ. Lodz ser. II, (60), p. 275Kasahara, Torri, Yuda, (1979) 16th Int. Cosmic-ray Conf., 13, p. 70Kasahara, Torii, Yuda, (1979) 16th Int. Cosmic-ray Conf., 13, p. 79Shibata, (1979) 16th Int. Cosmic-ray Conf., 7, p. 176H. Semba, T. Shibata and T. Tabuki, Suppl. Prog. Theor. Phys., to be publishedZhdanov, Roinishvilli, Smorodin, Tomaszevski, (1975) FIAN preprint no. 163Lattes, Fujimoto, Hasegawa, Hadronic interactions of high energy cosmic-ray observed by emulsion chambers (1980) Physics Reports, 65, p. 152Ellsworth, Gaisser, Yodh, (1981) Phys. Rev., 23 D, p. 764Baradzei, Smorodin, (1974) FIAN preprint nos. 103, 104Baradzei, Smorodin, (1977) Acta Univ. Lodz ser. II, (60), p. 51Zhdanov, (1980) FIAN preprint no. 140H. Semba, T. Shibata and T. Tabuki, Suppl. Prog. Theor. Phys., to be publishedShibata, (1980) Phys. Rev., 22 D, p. 100Slavatinsky, (1980) Proc. 7th European Symp. on Cosmic rays, , Leningrad, to be published(1979) AIP Conference Proc. no. 49, p. 145Azimov, Abduzhamilov, Chudakov, (1963) JETP (Sov. Phys.), 45, p. 40713th Int. Cosmic-ray Conf. (1973) 13th Int. Cosmic-ray Conf., 5, p. 326Acharya, Rao, Sivaprasad, Rao, (1979) 16th Int. Cosmic-ray Conf., 6, p. 289Ellsworth, Goodman, Yodh, Gaisser, Stanev, (1981) Phys. Rev., 23 D, p. 771Bariburina, Guseva, Denisova, (1980) Acta Univ. Lodz, 1, p. 9415th Int. Cosmic-ray Conf. (1977) 15th Int. Cosmic-ray Conf., 7, p. 184(1979) AIP Conf. Proc. no. 49, p. 33