MicroED as a Powerful Tool for Structure Determination of Macrocyclic Drug Compounds Directly from Their Powder Formulations.
- Resource Type
- Academic Journal
- Authors
- Danelius E; Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California 90095, United States.; Department of Biological Chemistry, University of California Los Angeles, 615 Charles E.Young Drive South, Los Angeles, California 90095, United States.; Bu G; Department of Biological Chemistry, University of California Los Angeles, 615 Charles E.Young Drive South, Los Angeles, California 90095, United States.; Wieske LHE; Department of Chemistry - BMC, Uppsala University, Husargatan 3, 75237 Uppsala, Sweden.; Gonen T; Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California 90095, United States.; Department of Biological Chemistry, University of California Los Angeles, 615 Charles E.Young Drive South, Los Angeles, California 90095, United States.; Department of Physiology, University of California Los Angeles, 615 Charles E. Young Drive South, Los Angeles, California 90095, United States.
- Source
- Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE
- Subject
- Language
- English
Macrocycles are important drug leads with many advantages including the ability to target flat and featureless binding sites as well as to act as molecular chameleons and thereby reach intracellular targets. However, due to their complex structures and inherent flexibility, macrocycles are difficult to study structurally, and there are limited structural data available. Herein, we use the cryo-EM method MicroED to determine the novel atomic structures of several macrocycles that have previously resisted structural determination. We show that structures of similar complexity can now be obtained rapidly from nanograms of material and that different conformations of flexible compounds can be derived from the same experiment. These results will have an impact on contemporary drug discovery as well as natural product exploration.