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Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
There are different ways in which membrane proteins can be associated with the phospholipid bilayer. Transmembrane proteins extend through the lipid bilayer and, like the lipids, are amphipathic, consisting of hydrophobic regions which interact with the lipid tails within the membrane, and hydrophilic regions that protrude the membrane and are exposed to water. This morphology is determined by the position and nature of the amino acid side chains. The final tertiary or quaternary structure of the protein will place side chains with polar functional groups to the outside in the regions exposed to water, while greasy side chains that are hydrophobic interact with the lipid membrane.
The Cell Membrane in the Steady State
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
A wide variety of protein molecules are associated with the cell membrane. They could be integral proteins that are part of the membrane, or peripheral proteins that temporarily attach either to the membrane or to the integral proteins. Integral proteins are of two types: Transmembrane proteins that extend across the membrane and form: (i) channels having aqueous pores, or “holes”, through which small molecules and ions can flow passively down an electrochemical potential gradient; (ii) ion transporters of various types that transport ions from one side of the membrane to the other, as explained in Section 2.3.Monotopic proteins, that is, proteins that are permanently attached to the cell membrane on only one side and do not extend across the membrane. These proteins are anchored to the membrane by having their hydrophobic regions extend into the fatty acid chain region of the membrane phospholipids.
Atomic Force Microscopy of Biomembranes
Published in Qiu-Xing Jiang, New Techniques for Studying Biomembranes, 2020
Yi Ruan, Lorena Redondo-Morata, Simon Scheuring
Integral membrane proteins, also known as transmembrane proteins, are embedded within the bilayer membranes of a cell, and are generally responsible for signal transduction, compound transport or channeling, etc. Importantly, most transmembrane proteins function with a conformational change as indicated by X-ray structures. However, a direct visualization of the conformational changes of a transmembrane protein remained elusive in static structures, nor can dynamic parameters be deduced from them. HS-AFM provides a unique method to probe membrane proteins in native-like lipid membranes. With the recent developments, it enables us to control the environment and resolve the details of conformational change of membrane proteins in real time.
Myosin light chain kinase regulates intestinal permeability of mucosal homeostasis in Crohn’s disease
Published in Expert Review of Clinical Immunology, 2020
TJ proteins are complex structures composed of more than 50 proteins, including a series of transmembrane proteins [68]. Transmembrane proteins mediate intercellular adhesion and seal the paracellular space. They include tetra-span and single-span proteins. Tetra-span proteins are composed of two extracellular loops and four transmembrane domains and include occludin, the claudin family, and tricellulin [69–71]. Plaque proteins, such as ZO-1, also have a role in the clustering and stabilization of transmembrane proteins. MLCK regulates the transmembrane proteins and associated proteins through its non-kinase activity to activate the TJ barrier, which controls intestinal permeability. The PAMR contributes to MLCK-dependent TJ regulation, which is the theoretical basis of targeting MLCK in a specific manner.
Functional mimetic of the G-protein coupled receptor CXCR4 on a soluble antibody scaffold
Published in mAbs, 2019
Adem C. Koksal, Meghan E. Pennini, Marcello Marelli, Xiaodong Xiao, William F. Dall’Acqua
GPCRs make up a large superfamily of more than 800 members, 150 of which have yet to be characterized functionally.39 They act in nearly all organs, making them valuable therapeutic targets40 in areas that include diabetes, inflammation, cancer, and the nervous system. Consequently, 40% of all marketed drugs target GPCR family members.41 However, most GPCRs are extremely difficult to express for further characterization. This approach sets the groundwork to generate GPCR surrogates that have antibody-like biochemical and biophysical characteristics, and offers an alternative for presenting ECLs for generation of novel therapeutics. This should help in understanding the structure/function relationship of multi-transmembrane proteins of interest, and in the design of a novel class of drugs targeting the pathways controlled by these proteins.
Cannabis for cancer – illusion or the tip of an iceberg: a review of the evidence for the use of Cannabis and synthetic cannabinoids in oncology
Published in Expert Opinion on Investigational Drugs, 2019
The EGFR family of extracellular protein ligands includes the receptor tyrosine kinases EGFR, human epidermal growth factor receptor 2 (HER2/Neu), Her 3, Her 4. EGFR is an important transmembrane protein, as mutations in its expression may result in cancer, and inhibition of its signaling pathways prevent tumor spread. Fatty acid amide hydrolase (FAAH), a serine hydrolase that metabolizes N-acylethanolamines like AEA, OEA, and PEA, is known to be overexpressed in certain cancer cells and its inhibition can enhance patient survival. Blockage of FAAH raises the level of AEA, inhibiting the EGFR signaling pathway and leading to cell arrest and apoptosis [61]. Both in vivo and in vitro, activation of CB2 receptors decreased migration and invasion of estrogen positive and negative breast cancer cells by suppressing EGFR and insulin-like growth factor tumorigenic pathways [62].