title: 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.
abstract: 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 α-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.
authors.affiliation: Department of Biochemistry, UMCN 286, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. w.degrip@ncmls.ru.nl
authors.forename: Willem J
authors.initials: WJ
authors.lastname: deGrip
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Bovee-Geurts
authors.forename: Yajie
authors.initials: Y
authors.lastname: Wang
authors.forename: Michiel A
authors.initials: MA
authors.lastname: Verhoeven
authors.forename: Johan
authors.initials: J
authors.lastname: Lugtenburg
mesh_terms: D000818:Animals; D002417:Cattle; D003521:Cyclopropanes / Q000737:chemistry*; D004224:Diterpenes; D008968:Molecular Conformation; D012168:Retinal Pigments / Q000737:chemistry* / Q000378:metabolism; D012172:Retinaldehyde / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry* / Q000378:metabolism; D012374:Rod Cell Outer Segment / Q000187:drug effects; D017550:Spectroscopy, Fourier Transform Infrared; D013237:Stereoisomerism; D015293:Transducin / Q000187:drug effects
chemical_list: D003521:Cyclopropanes; D004224:Diterpenes; D012168:Retinal Pigments; C042882:isorhodopsin; C031390:9-cis-retinal; D012243:Rhodopsin; D015293:Transducin; D012172:Retinaldehyde