Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compounds
文献类型：期刊论文
| 作者 | Ahmed, Lucky3; Ozbil, Mehmet3; Sekharan, Sivakumar3; Ten, Nicholas3; Batista, Victor S.3; Zhang, Yuetian4; Pan, Yi4; Zhang, Ruina4; Zhuang, Hanyi4; Block, Eric1 |
| 刊名 | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
 |
| 出版日期 | 2018 |
| 卷号 | 115期号:17页码:E3950-E3958 |
| 关键词 | olfaction odorant receptor musk quantum mechanics molecular dynamics |
| ISSN号 | 0027-8424 |
| DOI | 10.1073/pnas.1713026115 |
| 文献子类 | Article |
| 英文摘要 | Understanding olfaction at the molecular level is challenging due to the lack of crystallographic models of odorant receptors (ORs). To better understand the molecular mechanism of OR activation, we focused on chiral (R)-muscone and other musk-smelling odorants due to their great importance and widespread use in perfumery and traditional medicine, as well as environmental concerns associated with bioaccumulation of musks with estrogenic/antiestrogenic properties. We experimentally and computationally examined the activation of human receptors OR5AN1 and OR1A1, recently identified as specifically responding to musk compounds. OR5AN1 responds at nanomolar concentrations to musk ketone and robustly to macrocyclic sulfoxides and fluorine-substituted macrocyclic ketones; OR1A1 responds only to nitromusks. Structural models of OR5AN1 and OR1A1 based on quantum mechanics/molecular mechanics (QM/MM) hybrid methods were validated through direct comparisons with activation profiles from site-directed mutagenesis experiments and analysis of binding energies for 35 musk-related odorants. The experimentally found chiral selectivity of OR5AN1 to (R)-over (S)-muscone was also computationally confirmed for muscone and fluorinated (R)-muscone analogs. Structural models show that OR5AN1, highly responsive to nitromusks over macrocyclic musks, stabilizes odorants by hydrogen bonding to Tyr260 of transmembrane alpha-helix 6 and hydrophobic interactions with surrounding aromatic residues Phe105, Phe194, and Phe207. The binding of OR1A1 to nitromusks is stabilized by hydrogen bonding to Tyr258 along with hydrophobic interactions with surrounding aromatic residues Tyr251 and Phe206. Hydrophobic/nonpolar and hydrogen bonding interactions contribute, respectively, 77% and 13% to the odorant binding affinities, as shown by an atom-based quantitative structure-activity relationship model. |
| 学科主题 | Science & Technology - Other Topics |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; MAMMALIAN ODORANT RECEPTORS ; SITE-DIRECTED MUTAGENESIS ; MOUSE OLFACTORY RECEPTOR ; MACROCYCLIC KETONES ; RING EXPANSION ; TRANSMEMBRANE HELICES ; EFFICIENT SYNTHESIS ; VIBRATIONAL THEORY ; CF2 GROUP |
| 语种 | 英语 |
| WOS记录号 | WOS:000430697500014 |
| 出版者 | NATL ACAD SCIENCES |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/995]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所 |
| 作者单位 | 1.SUNY Albany, Dept Chem, Albany, NY 12222 USA; 2.Univ Estadual Campinas, Chem Inst, Dept Organ Chem, BR-13083970 Campinas, SP, Brazil; 3.Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA; 4.Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis, Dept Pathophysiol, Chinese Minist Educ,Sch Med, Shanghai 200025, Peoples R China; 5.Shanghai Jiao Tong Univ, Inst Hlth Sci, Sch Med, Shanghai Inst Biol Sci,Chinese Acad Sci, Shanghai 200031, Peoples R China, 6.China Agr Univ, Coll Sci, Dept Appl Chem, Beijing 100193, Peoples R China; 7.Duke Univ, Med Ctr, Dept Neurobiol, Duke Inst Brain Sci, Durham, NC 27710 USA; 8.Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA; 9.Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland; |
| 推荐引用方式 GB/T 7714 | Ahmed, Lucky,Ozbil, Mehmet,Sekharan, Sivakumar,et al. Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compounds[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2018,115(17):E3950-E3958. |
| APA | Ahmed, Lucky.,Ozbil, Mehmet.,Sekharan, Sivakumar.,Ten, Nicholas.,Batista, Victor S..,...&,.(2018).Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compounds.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,115(17),E3950-E3958. |
| MLA | Ahmed, Lucky,et al."Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compounds".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 115.17(2018):E3950-E3958. |
入库方式： OAI收割
来源：上海营养与健康研究所
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