Tetrahydrocarbazoles are a novel class of potent P-type ATPase inhibitors with antifungal activity.
Maike Bublitz,Lasse Kjellerup,Karen O'Hanlon Cohrt,Sandra Gordon,Anne Louise Mortensen,Johannes D. Clausen,Thomas David Pallin,John Bondo Hansen,Anja T. Fuglsang,William Dalby-Brown,Anne-Marie Lund Winther +10 more
TLDR
It is found that tetrahydrocarbazoles inhibit adenosine triphosphate (ATP) hydrolysis of thefungal H+-ATPase, depolarize the fungal plasma membrane and exhibit broad-spectrum antifungal activity.Abstract:
We have identified a series of tetrahydrocarbazoles as novel P-type ATPase inhibitors. Using a set of rationally designed analogues, we have analyzed their structure-activity relationship using functional assays, crystallographic data and computational modeling. We found that tetrahydrocarbazoles inhibit adenosine triphosphate (ATP) hydrolysis of the fungal H+-ATPase, depolarize the fungal plasma membrane and exhibit broad-spectrum antifungal activity. Comparative inhibition studies indicate that many tetrahydrocarbazoles also inhibit the mammalian Ca2+-ATPase (SERCA) and Na+,K+-ATPase with an even higher potency than Pma1. We have located the binding site for this compound class by crystallographic structure determination of a SERCA-tetrahydrocarbazole complex to 3.0 A resolution, finding that the compound binds to a region above the ion inlet channel of the ATPase. A homology model of the Candida albicans H+-ATPase based on this crystal structure, indicates that the compounds could bind to the same pocket and identifies pocket extensions that could be exploited for selectivity enhancement. The results of this study will aid further optimization towards selective H+-ATPase inhibitors as a new class of antifungal agents.read more
Citations
More filters
Journal ArticleDOI
Molecular Characterization of Carbapenem Resistant Klebsiella pneumoniae and Klebsiella quasipneumoniae Isolated from Lebanon.
TL;DR: Mining the completely sequenced K. pneumoniae genomes revealed the key roles of mobile genetic elements in the spread of antibiotic resistance and in understanding the epidemiology of these clinically significant pathogens.
Journal ArticleDOI
Sarco/Endoplasmic Reticulum Calcium ATPase Inhibitors: Beyond Anticancer Perspective.
TL;DR: This review brings an up-to-date comprehensive overview of recently discovered compounds with the potential of SERCA inhibition, discusses their mechanism of action, and highlights their potential clinical applications, such as cancer treatment.
Journal ArticleDOI
Linking Biochemical and Structural States of SERCA: Achievements, Challenges, and New Opportunities
TL;DR: An overview of the crystal structures of SERCA is provided, focusing on identifying metrics that facilitate structure-based categorization of major steps along the catalytic cycle, and the integration of crystallographic data with different biophysical approaches and computational methods to link biochemical and structural states ofSERCA that are populated in the cell are examined.
Journal ArticleDOI
Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia.
Matteo Marchesini,Andrea Gherli,Anna Montanaro,Laura Patrizi,Claudia Sorrentino,Luca Pagliaro,Chiara Rompietti,Samuel Kitara,Sabine Heit,Claus Olesen,Jesper V. Møller,Monia Savi,Leonardo Bocchi,Rocchina Vilella,Federica Rizzi,Marilena Baglione,Giorgia Rastelli,Caterina Loiacono,Roberta La Starza,Cristina Mecucci,Kimberly Stegmaier,Kimberly Stegmaier,Franco Aversa,Donatella Stilli,Anne-Marie Lund Winther,Paolo Sportoletti,Maike Bublitz,William Dalby-Brown,Giovanni Roti +28 more
TL;DR: CAD204520, a small molecule with better drug-like properties and reduced off-target Ca2+ toxicity compared with the SERCA inhibitor thapsigargin, is identified and preferentially targets mutated over wild-type NOTCH1 proteins in T cell acute lymphoblastic leukemia and mantle cell lymphoma.
Journal ArticleDOI
Structure and activation mechanism of the hexameric plasma membrane H+-ATPase.
TL;DR: In this paper, a high-resolution cryo-EM study of native Pma1 hexamers embedded in endogenous lipids was performed and it was shown that the Pma 1 hexamer encircles a liquid-crystalline membrane domain composed of 57 ordered lipid molecules.
References
More filters
Journal ArticleDOI
Coot: model-building tools for molecular graphics.
Paul Emsley,Kevin Cowtan +1 more
TL;DR: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics.
Journal ArticleDOI
AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility
Garrett M. Morris,Ruth Huey,William Lindstrom,Michel F. Sanner,Richard K. Belew,David S. Goodsell,Arthur J. Olson +6 more
TL;DR: AutoDock4 incorporates limited flexibility in the receptor and its utility in analysis of covalently bound ligands is reported, using both a grid‐based docking method and a modification of the flexible sidechain technique.
Book ChapterDOI
Phenix - a comprehensive python-based system for macromolecular structure solution
Paul D. Adams,Paul D. Adams,Pavel V. Afonine,Gábor Bunkóczi,Vincent B. Chen,Ian W. Davis,Nathaniel Echols,Jeffrey J. Headd,Li-Wei Hung,Gary J. Kapral,Ralf W. Grosse-Kunstleve,Airlie J. McCoy,Nigel W. Moriarty,Robert D. Oeffner,Randy J. Read,David S. Richardson,Jane S. Richardson,Thomas C. Terwilliger,Peter H. Zwart +18 more
TL;DR: PHENIX has been developed to provide a comprehensive system for macromolecular crystallographic structure solution with an emphasis on the automation of all procedures.
Journal ArticleDOI
Hidden Killers: Human Fungal Infections
Gordon D. Brown,David W. Denning,Neil A. R. Gow,Stuart M. Levitz,Mihai G. Netea,Theodore C. White +5 more
TL;DR: The importance of fungi as human pathogens is highlighted and the challenges the authors face in combating the devastating invasive infections caused by these microorganisms are discussed, in particular in immunocompromised individuals.
Journal ArticleDOI
Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 Å resolution
TL;DR: Comparison with a low-resolution electron density map of the enzyme in the absence of calcium and with biochemical data suggests that large domain movements take place during active transport.