Detailed description of the conformation and location of membrane-bound erythromycin A using isotropic bicelles

Nobuaki Matsumori, Atsushi Morooka, Michio Murata

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Although many nonpeptidic drugs target biological membrane and membrane proteins, it is still difficult to define the membrane-bound structure of the drugs. In this study, we utilized bicelles as a membrane model, since the bicelles, which have planar lipid bilayer portions, are thought to be a more appropriate and practical membrane model than micelles. Bicelles with a small diameter allow for measurements of liquid NMR due to fast tumbling in solution. We targeted erythromycin A (EA) as a membrane-binding compound because it is pointed out that the drug interacts with lysosomal membranes, inhibits phospholipase A, and consequently induces phospholipidosis as a side effect. The conformation of EA in the bicelle was successfully determined on the basis of coupling constants and NOEs. Measurements of intermolecular NOEs and paramagnetic relaxation times revealed that the drug is located shallowly in the membrane surface, with the dimethylamino group being close to the phosphate, and the macrolide portion adjacent to upper sides of the acyl chains. This study shows the general utility of isotropic bicelles for detailed conformational and orientational studies of membrane-associated nonpeptidic drugs.

Original languageEnglish
Pages (from-to)3501-3508
Number of pages8
JournalJournal of Medicinal Chemistry
Volume49
Issue number12
DOIs
Publication statusPublished - Jun 15 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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