Article
Biology
Xiaochen Chen, Lu Wang, Qianqian Cui, Zhanyu Ding, Li Han, Yongjun Kou, Wenqing Zhang, Haonan Wang, Xiaomin Jia, Mei Dai, Zhenzhong Shi, Yuying Li, Xiyang Li, Yong Geng
Summary: The human calcium-sensing receptor (CaSR) maintains Ca2+ homeostasis and structurally transitions through multiple intermediate states during activation. Binding of agonists leads to conformational changes and compaction of the dimer, ultimately activating the receptor.
Article
Multidisciplinary Sciences
Ruth A. Pumroy, Anna D. Protopopova, Tabea C. Fricke, Iris U. Lange, Ferdinand M. Haug, Phuong T. Nguyen, Pamela N. Gallo, Barbara B. Sousa, Goncalo J. L. Bernardes, Vladimir Yarov-Yarovoy, Andreas Leffler, Vera Y. Moiseenkova-Bell
Summary: The study identifies a binding site for the activator 2-APB in TRPV2 and confirms the role of His521 and Arg539 in the activation process. Additionally, it shows that the combination of 2-APB and cannabidiol has a synergetic effect on TRPV2 activation.
NATURE COMMUNICATIONS
(2022)
Review
Neurosciences
Tomoyuki Kuwaki, Nobuaki Takahashi
Summary: TRPA1 is a member of the TRP superfamily of cation channels and is widely expressed in sensory neural pathways. It detects irritant chemicals, hypoxia, and hyperoxia. Its role in respiratory and behavioral modulation has been studied using Trpa1 knockout mice. The results show that TRPA1 is necessary for protective responses in respiration and behavior, suggesting that TRPA1 channels in the airway may play a sentinel role for environmental threats.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Editorial Material
Neurosciences
Michael Fine, Xiaochun Li
Summary: TRPA1 is identified as a promising target for novel treatments of chronic pain. The study introduces a new non-covalent TRPA1-biased agonist, GNE551, which reveals a unique binding pocket and activation properties that lay the groundwork for new avenues in chronic pain treatment.
Article
Multidisciplinary Sciences
Wolfram Seifert-Davila, Mathias Girbig, Luis Hauptmann, Thomas Hoffmann, Sebastian Eustermann, Christoph W. Mueller
Summary: Transcription factor (TF) IIIC recruits RNA polymerase (Pol) III to target genes by recognizing intragenic A- and B-box motifs. Cryo-electron microscopy structures revealed that the tau B module of TFIIIC recognizes the B-box through DNA shape and sequence readout. TFIIIC220 acts as a linker connecting the tau A and tau B subcomplexes, facilitating scanning for A-boxes and Pol III activation by TFIIIB.
Article
Biochemistry & Molecular Biology
Gaurika Garg, Christian Dienemann, Lucas Farnung, Juliane Schwarz, Andreas Linden, Henning Urlaub, Patrick Cramer
Summary: We provide mechanistic insights into the three major steps of human co-transcriptional pre-mRNA capping based on six different cryo-EM structures. The human mRNA capping enzyme, RNGTT, first docks to the Pol II stalk to position its triphosphatase domain near the RNA exit site. The capping enzyme then moves onto the Pol II surface, and its guanylyltransferase receives the pre-mRNA 5'-diphosphate end.
Article
Cell Biology
Yamuna Kalyani Mathiharan, Ian W. Glaaser, Yulin Zhao, Michael J. Robertson, Georgios Skiniotis, Paul A. Slesinger
Summary: This study demonstrates how cholesterol affects the structure of GIRK2 channels, revealing that cholesterol modulates the channel by stabilizing the interaction between PIP2 and the channel. This finding may contribute to the development of therapeutics for neurological diseases.
Review
Cell Biology
Yang Li, Xue Yang, Yuequan Shen
Summary: Orai channels, belonging to the CRAC channel family, play a crucial role in Ca2+ influx triggered by ER Ca2+ depletion. While structural and functional studies have advanced our understanding of Orai channel activation, the gating mechanism for Ca2+ permeation remains less well understood. This review summarizes existing structural studies, detailing features, comparing closed and open states, and proposing a push-pull model for Ca2+ permeation.
Article
Biology
Luba Mahbub, Guennadi Kozlov, Pengyu Zong, Emma L. Lee, Sandra Tetteh, Thushara Nethramangalath, Caroline Knorn, Jianning Jiang, Ashkan Shahsavan, Lixia Yue, Loren Runnels, Kalle Gehring
Summary: ARL15 is a GTP and CNNM-binding protein that inhibits Mg2+ efflux and competes with PRLs for binding to CNNM, thereby coordinating regulation of ion transport by CNNM and TRPM7.
Article
Biotechnology & Applied Microbiology
Yuru Tong, Xiaoli Ma, Tianyuan Hu, Kang Chen, Guanghong Cui, Ping Su, Haifeng Xu, Wei Gao, Tao Jiang, Luqi Huang
Summary: In this study, the intermediate of Selaginella moellendorffii miltiradiene synthase (SmMDS) synthesis was confirmed through mutagenesis studies. The contribution of key residues in active sites and the transport of intermediates between different active sites were analyzed. The research provides new insights into the mechanism and regulation of diterpene synthesis.
PLANT BIOTECHNOLOGY JOURNAL
(2023)
Article
Multidisciplinary Sciences
Yuyuan Zheng, Lei Ding, Xianhui Meng, Meg Potter, Alison L. Kearney, Jie Zhang, Jie Sun, David E. James, Guang Yang, Chun Zhou
Summary: Research has revealed that SIN1 is a vital component of mTORC2 and can interact with Ras family small GTPases through its Ras-binding domain (RBD). The association between Ras and SIN1/mTORC2 can potentially impact both mTORC2 and Ras-ERK pathways. By determining the high-resolution structures of HRas/KRas-SIN1 RBD complexes, researchers have identified the detailed interaction interface. Mutations in critical interface residues disrupt the Ras-SIN1 interaction, and in SIN1 knockout cells, it has been shown that the Ras-SIN1 association promotes SGK1 activity but inhibits insulin-induced ERK activation. Comparison with other Ras-binding proteins and experimental assays suggest that the association between HRas and SIN1 RBD is weaker than HRas-Raf1 RBD but slightly stronger than HRas-PI3K RBD, potentially explaining the different outcomes of insulin or EGF stimulation. Additionally, a Ras dimerization interface critical for Ras oligomerization has been uncovered. These findings contribute to our understanding of the Ras-SIN1 association and the cross-talk between growth factor-stimulated pathways.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Yan Zhang, Xiaoyun Pang, Jian Li, Jiashu Xu, Victor W. Hsu, Fei Sun
Summary: By using cryoelectron microscopy, researchers have revealed the protein lattice formed by SNX1, which helps to understand how it functions in generating transport carriers. Comparing the structure of SNX1 with that of an endosomal coat complex formed by retromer coupled to a SNX provides insights into the molecular organization of SNX and the intermediary stages of assembly leading to the formation of the complex on the membrane.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Masaki Matsubara, Yukiko Muraki, Noriyuki Hatano, Hiroka Suzuki, Katsuhiko Muraki
Summary: The synthetic compound JT010 selectively activates human TRPA1 (hTRPA1) but has little effect on mouse TRPA1 (mTRPA1). This finding is important for understanding the function of TRPA1 and the mechanisms involved in inflammatory pain sensation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Pharmacology & Pharmacy
David Machalz, Szymon Pach, Marcel Bermudez, Matthias Bureik, Gerhard Wolber
Summary: This review summarizes recent structural insights into understudied cytochrome P450 enzymes, highlighting the impact of molecular modeling for mechanistically explaining pathophysiological effects and establishing understudied CYPs as promising drug targets.
DRUG DISCOVERY TODAY
(2021)
Article
Biology
Fenghui Zhao, Chao Zhang, Qingtong Zhou, Kaini Hang, Xinyu Zou, Yan Chen, Fan Wu, Qidi Rao, Antao Dai, Wanchao Yin, Dan-Dan Shen, Yan Zhang, Tian Xia, Raymond C. Stevens, H. Eric Xu, Dehua Yang, Lihua Zhao, Ming-Wei Wang
Summary: This study presents the cryo-EM structure of human GIPR in complex with GIP and a G(s) trimer, revealing a structural framework of hormone recognition and GIPR activation. It shows the specific interactions between GIP and GIPR that contribute to their metabolic functions.