Article
Multidisciplinary Sciences
Fenghui Guan, Tianyu Li, Wei Dong, Rui Guo, Hao Chai, Zhiqiu Chen, Zhong Ren, Yang Li, Sheng Ye
Summary: This study reveals the allosteric mechanism of MthK through analyzing its structure and conducting thermodynamic and electrophysiological measurements. The study found that the conformations of the Ca2+-binding sites in MthK alternate between two quaternary states and exhibit significant differences in Ca2+ affinity. An allosteric model of MthK gating mechanism is proposed, in which a cascade of structural events connect the initial Ca2+-binding to the final changes of the ring structure that open the ion-conduction pore. This mechanical model sheds light on the design of allosteric gating and its potential relevance for other ligand-gated ion channels containing the RCK domain.
NATIONAL SCIENCE REVIEW
(2022)
Article
Multidisciplinary Sciences
Shira Burg, Shir Shapiro, Asher Peretz, Elvira Haimov, Boris Redko, Adva Yeheskel, Luba Simhaev, Hamutal Engel, Avi Raveh, Ariel Ben-Bassat, Michael Murninkas, Rotem Polak, Yoni Haitin, Yoram Etzion, Bernard Attali
Summary: Phosphatidylinositol 4-5 bisphosphate (PIP2) potently activates the SK4 channel by docking to the boundary of the CaM-binding domain. An allosteric blocker, BA6b9, inhibits SK4 channels by interacting with specific residues in the linker S4-S5, preventing proper interaction between the Ca2+-CaM N-lobe and the channel linker region. Inhibition of SK4 channels by targeting drugs to the CaM-PIP2-binding domain may serve as a promising anti-arrhythmic therapy.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Michael Brundl, Sarala Pellikan, Anna Stary-Weinzinger
Summary: ATP-sensitive potassium (K-ATP) channels consist of Kir6.2 pore and SUR domains, dysfunction linked to diseases, gating regulated by conformational changes and ligands including PIP2 activation. Structural information combined with functional data reveals the mechanism underlying Kir6.2 channel regulation by PIP2.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Multidisciplinary Sciences
Janik B. Hedderich, Margherita Persechino, Katharina Becker, Franziska M. Heydenreich, Torben Gutermuth, Michel Bouvier, Moritz Buenemann, Peter Kolb
Summary: Researchers computationally describe alternative allosteric pockets in G-protein-coupled receptors, identifying nine previously untargeted sites for synthetic ligands. They further investigate the potential of modulating receptor function through ligand binding to these sites.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Physical
Ashan Dayananda, T. S. Hayden Dennison, Hewafonsekage Yasan Y. Fonseka, Mohammad S. Avestan, Qi Wang, Riina Tehver, George Stan
Summary: Proteolysis is crucial for regulating metabolic pathways and the cell cycle. Bacterial caseinolytic proteases (Clp) use peptidase components, such as ClpP, to degrade defective proteins and control stress-response proteins. The opening of the proteolytic chamber is controlled by a gating mechanism of the axial pores, triggered by Clp ATPase or small molecules like acyldepsipeptide (ADEP). This study explores the allosteric communication underlying the conformational changes and the rewiring of the allosteric pathways in the open-closed pore transition.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Pedro Renault, Jesus Giraldo
Summary: Computational tools have been used to estimate the druggability of allosteric sites in GPCRs, but predicting hydrophobic sites remains challenging. This study introduces a dynamics-based approach using experimental structures, normal mode analysis, and molecular dynamics simulations to identify allosteric sites in beta 2AR, GCGR, and M2 receptors, showing promising predictive value.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Takushi Shimomura, Kiichi Hirazawa, Yoshihiro Kubo
Summary: This study reveals that different conformations of DII-S4 determine the gating modes in Two-pore channels (TPCs), with the intermediate state representing the PIP2-gating mode. TPC3 is primarily voltage-dependent, while TPC2 is PIP2-gated and nonvoltage-dependent. Furthermore, the antidepressant desipramine induces voltage dependence in TPC2, and the flavonoid naringenin biases the mode preference from PIP2-gating to desipramine-induced voltage gating.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Biochemistry & Molecular Biology
Efpraxia Tzortzini, Antonios Kolocouris
Summary: Most membrane lipids interact with GPCRs structures and modulate their function. PIP2 and cholesterol have an impact on the conformational equilibria of the A(2A) adenosine receptor.
Article
Biochemistry & Molecular Biology
I. Can Kazan, Jeremy H. Mills, S. Banu Ozkan
Summary: We investigated the relationship between mutations and dynamics in Escherichia coli dihydrofolate reductase (DHFR) using computational methods. Our study used molecular dynamics simulations and developed position-specific metrics to analyze the dynamics of wild-type DHFR. We found a significant association between dynamic flexibility and mutational tolerance of DHFR positions, and identified residues that control the dynamics of specific loops. These findings can help predict functionally beneficial or detrimental substitutions and guide rational enzyme engineering.
Article
Multidisciplinary Sciences
Ruitao Jin, Sitong He, Katrina A. Black, Oliver B. Clarke, Di Wu, Jani R. Bolla, Paul Johnson, Agalya Periasamy, Ahmad Wardak, Peter Czabotar, Peter M. Colman, Carol Robinson, Derek Laver, Brian J. Smith, Jacqueline M. Gulbis
Summary: This paper reveals the gating mechanism of potassium channels and how ion conduction is controlled by anionic lipids. The study demonstrates that anionic lipids interact with the steric plug within the ion conduction pathway, operating the gate. This research is of great significance for our understanding of the gating mechanism of potassium channels.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Longmei Li, Jin Zhang, Wenjing Sun, Weimin Gong, Changlin Tian, Pan Shi, Chaowei Shi
Summary: This study used F-19 solution NMR spectroscopy to investigate the conformational changes of G proteins upon interaction with detergent mimicking membrane and receptor. The results showed that there are two equilibrium states in the Gain apo states, and the interaction with detergents accelerates the conformational transformation.
CHINESE CHEMICAL LETTERS
(2022)
Article
Multidisciplinary Sciences
Terra Sztain, Thomas G. Bartholow, D. John Lee, Lorenzo Casalino, Andrew Mitchell, Megan A. Young, Jianing Wang, J. Andrew McCammon, Michael D. Burkart
Summary: Enzymes in metabolic pathways utilize a variety of regulatory mechanisms to maintain homeostasis, with carrier proteins playing an essential role in substrate shuttling. A unique communication mechanism between ACP and partner enzymes has been demonstrated, showing allosteric regulation dependent on fatty acid chain length. These findings provide insights into cargo communication by ACP and can potentially be used for engineering carrier protein-dependent pathways for specific products.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Kevin M. Knight, Soumadwip Ghosh, Sharon L. Campbell, Tyler J. Lefevre, Reid H. J. Olsen, Alan Smrcka, Natalie H. Valentin, Guowei Yin, Nagarajan Vaidehi, Henrik G. Dohlman
Summary: Proteins are crucial in signal transduction and pharmacology, with G proteins playing a central role. Research has shown that a conserved network of amino acids dictates the release of G protein subunits, providing insights into the molecular basis of G protein activation.
Review
Biochemistry & Molecular Biology
Raudah Lazim, Donghyuk Suh, Jai Woo Lee, Thi Ngoc Lan Vu, Sanghee Yoon, Sun Choi
Summary: The presence of GPCR dimers has sparked research into their importance in disease pathogenesis and drug design, uncovering new signaling pathways and potential therapeutic targets. The increasing influence of computational methods in research is providing new avenues for understanding the functions and interactions of GPCRs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Wen-Hao Tsai, Cedric Grauffel, Ming-Yueh Huang, Sandra Postic, Marjan Slak Rupnik, Carmay Lim, Shi-Bing Yang
Summary: This study investigates the effect of extracellular pH on the gating mechanism of alkaline-activated K2P channel TALK1. The results show that R233 acts as the primary pH sensor and regulates the conformational changes of the potassium-binding site through an interacting network. The acidic pH-activated R233E mutant can recapitulate the network interactions of protonated R233. The data further suggest stochastic coupling between R233 and the SF gate.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)