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Title: Catalytic mechanism of a retinoid isomerase essential for vertebrate vision

Abstract

Visual function in vertebrates is dependent on the membrane-bound retinoid isomerase RPE65, an essential component of the retinoid cycle pathway that regenerates 11-cis-retinal for rod and cone opsins. The mechanism by which RPE65 catalyzes stereoselective retinoid isomerization has remained elusive because of uncertainty about how retinoids bind to its active site. Here we present crystal structures of RPE65 in complex with retinoid-mimetic compounds, one of which is in clinical trials for the treatment of age-related macular degeneration. The structures reveal the active site retinoid-binding cavity located near the membrane-interacting surface of the enzyme as well as an Fe-bound palmitate ligand positioned in an adjacent pocket. With the geometry of the RPE65–substrate complex clarified, we delineate a mechanism of catalysis that reconciles the extensive biochemical and structural research on this enzyme. Finally, these data provide molecular foundations for understanding a key process in vision and pharmacological inhibition of RPE65 with small molecules.

Authors:
 [1];  [1];  [1];  [1];  [2];  [1];  [1];  [1];  [1]
  1. Case Western Reserve Univ., Cleveland, OH (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States); Case Western Reserve Univ., Cleveland, OH (United States)
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1228942
Report Number(s):
BNL-111017-2015-JA
Journal ID: ISSN 1552-4450
Grant/Contract Number:  
SC00112704; AC02-06CH11357; MCB-084480; IK2BX002683; EY023948; EY009339; EY021126; CA157735
Resource Type:
Accepted Manuscript
Journal Name:
Nature Chemical Biology
Additional Journal Information:
Journal Volume: 11; Journal Issue: 6; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; enzyme mechanisms; lipids; neuroscience; x-ray crystallography

Citation Formats

Kiser, Philip D., Zhang, Jianye, Badiee, Mohsen, Li, Qingjiang, Shi, Wuxian, Sui, Xuewu, Golczak, Marcin, Tochtrop, Gregory P., and Palczewski, Krzysztof. Catalytic mechanism of a retinoid isomerase essential for vertebrate vision. United States: N. p., 2015. Web. doi:10.1038/nchembio.1799.
Kiser, Philip D., Zhang, Jianye, Badiee, Mohsen, Li, Qingjiang, Shi, Wuxian, Sui, Xuewu, Golczak, Marcin, Tochtrop, Gregory P., & Palczewski, Krzysztof. Catalytic mechanism of a retinoid isomerase essential for vertebrate vision. United States. https://doi.org/10.1038/nchembio.1799
Kiser, Philip D., Zhang, Jianye, Badiee, Mohsen, Li, Qingjiang, Shi, Wuxian, Sui, Xuewu, Golczak, Marcin, Tochtrop, Gregory P., and Palczewski, Krzysztof. Mon . "Catalytic mechanism of a retinoid isomerase essential for vertebrate vision". United States. https://doi.org/10.1038/nchembio.1799. https://www.osti.gov/servlets/purl/1228942.
@article{osti_1228942,
title = {Catalytic mechanism of a retinoid isomerase essential for vertebrate vision},
author = {Kiser, Philip D. and Zhang, Jianye and Badiee, Mohsen and Li, Qingjiang and Shi, Wuxian and Sui, Xuewu and Golczak, Marcin and Tochtrop, Gregory P. and Palczewski, Krzysztof},
abstractNote = {Visual function in vertebrates is dependent on the membrane-bound retinoid isomerase RPE65, an essential component of the retinoid cycle pathway that regenerates 11-cis-retinal for rod and cone opsins. The mechanism by which RPE65 catalyzes stereoselective retinoid isomerization has remained elusive because of uncertainty about how retinoids bind to its active site. Here we present crystal structures of RPE65 in complex with retinoid-mimetic compounds, one of which is in clinical trials for the treatment of age-related macular degeneration. The structures reveal the active site retinoid-binding cavity located near the membrane-interacting surface of the enzyme as well as an Fe-bound palmitate ligand positioned in an adjacent pocket. With the geometry of the RPE65–substrate complex clarified, we delineate a mechanism of catalysis that reconciles the extensive biochemical and structural research on this enzyme. Finally, these data provide molecular foundations for understanding a key process in vision and pharmacological inhibition of RPE65 with small molecules.},
doi = {10.1038/nchembio.1799},
journal = {Nature Chemical Biology},
number = 6,
volume = 11,
place = {United States},
year = {Mon Apr 20 00:00:00 EDT 2015},
month = {Mon Apr 20 00:00:00 EDT 2015}
}

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