4RYZ

Crystal structure of RPE65 in complex with S-emixustat and palmitate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Molecular pharmacodynamics of emixustat in protection against retinal degeneration.

Zhang, J.Kiser, P.D.Badiee, M.Palczewska, G.Dong, Z.Golczak, M.Tochtrop, G.P.Palczewski, K.

(2015) J Clin Invest 125: 2781-2794

  • DOI: https://doi.org/10.1172/JCI80950
  • Primary Citation of Related Structures:  
    4RYX, 4RYY, 4RYZ, 4ZHK

  • PubMed Abstract: 

    Emixustat is a visual cycle modulator that has entered clinical trials as a treatment for age-related macular degeneration (AMD). This molecule has been proposed to inhibit the visual cycle isomerase RPE65, thereby slowing regeneration of 11-cis-retinal and reducing production of retinaldehyde condensation byproducts that may be involved in AMD pathology. Previously, we reported that all-trans-retinal (atRAL) is directly cytotoxic and that certain primary amine compounds that transiently sequester atRAL via Schiff base formation ameliorate retinal degeneration. Here, we have shown that emixustat stereoselectively inhibits RPE65 by direct active site binding. However, we detected the presence of emixustat-atRAL Schiff base conjugates, indicating that emixustat also acts as a retinal scavenger, which may contribute to its therapeutic effects. Using agents that lack either RPE65 inhibitory activity or the capacity to sequester atRAL, we assessed the relative importance of these 2 modes of action in protection against retinal phototoxicity in mice. The atRAL sequestrant QEA-B-001-NH2 conferred protection against phototoxicity without inhibiting RPE65, whereas an emixustat derivative incapable of atRAL sequestration was minimally protective, despite direct inhibition of RPE65. These data indicate that atRAL sequestration is an essential mechanism underlying the protective effects of emixustat and related compounds against retinal phototoxicity. Moreover, atRAL sequestration should be considered in the design of next-generation visual cycle modulators.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Retinoid isomerohydrolase
A, B
533Bos taurusMutation(s): 1 
EC: 3.1.1.64 (PDB Primary Data), 5.3.3.22 (UniProt)
UniProt
Find proteins for Q28175 (Bos taurus)
Explore Q28175 
Go to UniProtKB:  Q28175
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ28175
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
A5V BindingDB:  4RYZ IC50: min: 55, max: 1000 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 175.603α = 90
b = 175.603β = 90
c = 86.323γ = 120
Software Package:
Software NamePurpose
XDSdata scaling
REFMACrefinement
XDSdata reduction
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-05-27
    Type: Initial release
  • Version 1.1: 2021-07-07
    Changes: Database references, Derived calculations
  • Version 1.2: 2024-11-27
    Changes: Data collection, Database references, Refinement description, Structure summary