Active site-directed inactivation of constitutively active mutants of rhodopsin

Recently, mutations of the active site Lys296 residue in rhodopsin (Lys296-->Glu and Lys296-->Met) have been found as the cause of disease in some patients with autosomal dominant retinitis pigmentosa. In vitro, these mutations result in constitutive activation of the protein. In an effort to...

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Bibliographic Details
Published in:The Journal of biological chemistry 1994-03, Vol.269 (9), p.6524-6527
Main Authors: GOVARDHAN, C. P, OPRIAN, D. D
Format: Article
Language:English
Subjects:
Amines - pharmacology
Amino Acid Sequence
Analytical, structural and metabolic biochemistry
Animals
Binding Sites
Biological and medical sciences
Cattle
Fundamental and applied biological sciences. Psychology
Humans
Kinetics
Lysine
Molecular Structure
Non metallic chromoproteins, photoproteins
Point Mutation
Proteins
Retinaldehyde - analogs & derivatives
Retinaldehyde - pharmacology
Retinitis Pigmentosa - genetics
Rhodopsin - antagonists & inhibitors
Rhodopsin - genetics
Structure-Activity Relationship
Transducin - antagonists & inhibitors
Transducin - metabolism
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Summary:Recently, mutations of the active site Lys296 residue in rhodopsin (Lys296-->Glu and Lys296-->Met) have been found as the cause of disease in some patients with autosomal dominant retinitis pigmentosa. In vitro, these mutations result in constitutive activation of the protein. In an effort to develop a potential therapeutic agent for treatment of the disease, we have examined various amine derivatives of 11-cis- and 9-cis-retinal for ability to irreversibly inactivate a related constitutively active mutant, K296G. Three amines were prepared by reductive amination of retinal: 11-cis-retinylpropylamine, 11-cis-retinylamine, and 9-cis-retinylamine. All three compounds inactivated K296G, and the inactivation could not be reversed upon exposure to light. None of the compounds inactivated the wild-type protein. Although the amines were not effective on the naturally occurring retinitis pigmentosa mutants, presumably because of unfavorable steric interactions with the bulky Glu and Met side chains at position 296, the success with K296G makes it highly encouraging that this approach will evolve related compounds that are capable of inactivating the naturally occurring mutants as well.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(17)37403-3