Cyclopropyl and isopropyl derivatives of 11-cis and 9-cis retinals at C-9 and C-13: subtle steric differences with major effects on ligand efficacy in rhodopsin
| Autor: | Yajie Wang, Johan Lugtenburg, Michiel A. Verhoeven, Petra H. M. Bovee-Geurts, Willem J. DeGrip |
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| Rok vydání: | 2011 |
| Předmět: |
Steric effects
Cyclopropanes Chemical and physical biology [NCMLS 7] Opsin Rhodopsin Stereochemistry Molecular Conformation Pharmaceutical Science Analytical Chemistry Drug Discovery Spectroscopy Fourier Transform Infrared Animals Transducin Binding site Pharmacology biology Ligand Chemistry Organic Chemistry Stereoisomerism Chromophore Rod Cell Outer Segment Complementary and alternative medicine biology.protein Retinaldehyde Molecular Medicine Cattle Diterpenes Retinal Pigments Isopropyl |
| Zdroj: | Journal of Natural Products, 74, 3, pp. 383-90 Journal of Natural Products, 74, 383-90 |
| ISSN: | 0163-3864 |
| Popis: | Item does not contain fulltext Retinal is the natural ligand (chromophore) of the vertebrate rod visual pigment. It occurs in either the 11-cis (rhodopsin) or the 9-cis (isorhodopsin) configuration. In its evolution to a G protein coupled photoreceptor, rhodopsin has acquired exceptional photochemical properties. Illumination isomerizes the chromophore to the all-trans isomer, which acts as a full agonist. This process is extremely efficient, and there is abundant evidence that the C-9 and C-13 methyl groups of retinal play a pivotal role in this process. To examine the steric limits of the C-9 and C-13 methyl binding pocket of the binding site, we have prepared C-9 and C-13 cyclopropyl and isopropyl derivatives of its native ligands and of alpha-retinal at C-9. Most isopropyl analogues show very poor binding, except for 9-cis-13-isopropylretinal. Most cyclopropyl derivatives exhibit intermediate binding activity, except for 9-cis-13-cyclopropylretinal, which presents good binding activity. In general, the binding site shows preference for the 9-cis analogues over the 11-cis analogues. In fact, 13-isopropyl-9-cis-retinal acts as a superagonist after illumination. Another surprising finding was that 9-cyclopropylisorhodopsin is more like native rhodopsin with respect to spectral and photochemical properties, whereas 9-cyclopropylrhodopsin behaves more like native isorhodopsin in these aspects. |
| Databáze: | OpenAIRE |
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