The long-chain fatty acid receptor FFAR1/GPR40 binds agonists in both an interhelical site between the extracellular segments of transmembrane helix (TM)-III and TM-IV and a lipid-exposed groove between the intracellular segments of these helices. Molecular dynamics simulations of FFAR1 with agonist removed demonstrated a major rearrangement of the polar and charged anchor point residues for the carboxylic acid moiety of the agonist in the interhelical site, which was associated with closure of a neighboring, solvent-exposed pocket between the extracellular poles of TM-I, TM-II, and TM-VII. A synthetic compound designed to bind in this pocket, and thereby prevent its closure, was identified through structure-based virtual screening and shown to function both as an agonist and as an allosteric modulator of receptor activation. This discovery of an allosteric agonist for a previously unexploited, dynamic pocket in FFAR1 demonstrates both the power of including molecular dynamics in the drug discovery process and that this specific, clinically proven, but difficult, antidiabetes target can be addressed by chemotypes different from existing ligands.
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http://dx.doi.org/10.1073/pnas.1811066116 | DOI Listing |
Appl Magn Reson
March 2024
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Site-directed spin labeling (SDSL) has been invaluable in the analysis of protein structure and dynamics, and has been particularly useful in the study of membrane proteins. ExoU, an important virulence factor in infections, is a bacterial phospholipase A2 that functions at the membrane - aqueous interface. Using SDSL methodology developed in the Hubbell lab, we find that the region surrounding the catalytic site of ExoU is buried within the tertiary structure of the protein in the soluble, apoenzyme state, but shows a significant increase in dynamics upon membrane binding and activation by ubiquitin.
View Article and Find Full Text PDFIndian J Otolaryngol Head Neck Surg
September 2023
Department of Plastic, Reconstructive and Faciomaxillary Surgery, Madras Medical College, Chennai, 600003 India.
Reconstruction of upper third helico-scaphal defects (HSDs) exacts the expertise of the reconstructive surgeon. These three-dimensional defects deviate from normal facial form and cause a significant impact on the psyche of the patients. The origin, course, and dimensions of the perforators of the Eril's branch arising from superficial temporal vessels (EBSTV) were delineated by dissection and injection study.
View Article and Find Full Text PDFBiomolecules
April 2023
Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529, USA.
Intrinsically disordered proteins play important roles in cell signaling, and dysregulation of these proteins is associated with several diseases. Prostate apoptosis response-4 (Par-4), an approximately 40 kilodalton proapoptotic tumor suppressor, is a predominantly intrinsically disordered protein whose downregulation has been observed in various cancers. The caspase-cleaved fragment of Par-4 (cl-Par-4) is active and plays a role in tumor suppression by inhibiting cell survival pathways.
View Article and Find Full Text PDFJ Antimicrob Chemother
June 2023
College of Science and Engineering, Flinders University, Bedford Park, SA 5042, Australia.
Nat Commun
January 2023
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
The Zrt-/Irt-like protein (ZIP) family consists of ubiquitously expressed divalent metal transporters critically involved in maintaining systemic and cellular homeostasis of zinc, iron, and manganese. Here, we present a study on a prokaryotic ZIP from Bordetella bronchiseptica (BbZIP) by combining structural biology, evolutionary covariance, computational modeling, and a variety of biochemical assays to tackle the issue of the transport mechanism which has not been established for the ZIP family. The apo state structure in an inward-facing conformation revealed a disassembled transport site, altered inter-helical interactions, and importantly, a rigid body movement of a 4-transmembrane helix (TM) bundle relative to the other TMs.
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