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This Sandbox is Reserved from Jan 13 through July 31, 2020 for use in the course Protein Structure in Drug Discovery taught by Karen C. Glass at the ACPHS, Colchester, United States. This reservation includes Sandbox Reserved 895 through Sandbox Reserved 901.

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Contents 1 1. Introduction 1.1 (S)-Emixustat 1.2 R/S Enantiomers Differences 2 Disease Implications 3 Medical Relevance 3.1 Dry (atrophic) age related macular degeneration 3.2 Stargadt's Disease 4 References

1. Introduction

In humans the vertebrate vision is maintained by a chemical process known as the retinoid (visual) cycle. This cycle is a complex enzymatic pathway that operates within the retina to regenerate a key visual chromophore known as 11-cis-retinal. The enzyme responsible for regenerating the key visual chromophore, 11-cis-retinal is a microsomal membrane protein retinal pigment epithelium 65 also known as RPE65. The RPE65 enzyme catalyzes the chemical conversion of all-trans-retinyl ester (or all-trans-retinyl palmityl ester) to 11-cis-retinol within the human retinal pigment epithelium (hRPE). RPE65 is located within the hRPE cells located in the back of the eye. The human retinal pigment epithelium is responsible for regulating the nourishment of the retina. Since the retinoid (visual) cycle requires the incorporation of light into catalyzing chemical reactions, hRPE cells are light sensitive.

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spinqualitylabelsall models Figure 1: Emixustat and palmitate bound in the active site of RPE65 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 Structure and Activity 1.1 Classification and Structural Analysis of RPE65 1.2 Enzymatic Activity of RPE65 2 Protein-Ligand Interaction 2.1 Endogenous Ligand 2.2 Exogenous Ligand 2.2.1 (R)-Emixustat (ACU-4429) Structure and Activity Classification and Structural Analysis of RPE65 Classification nomenclature for RPE65 is as follow according to <insert classification type> Retinal pigment epithelium 65 (RPE65) resembles a 7-bladed propeller with two deep binding pockets that contains a lipophilic binding pocket (which binds to endogenous palmitoyl acid) as well as an charged iron(II) atom stabilized by 4 histidine residues (His180, His241, His313 and His527) which binds to the carboxylic acid functional group of endogenous palmitoyl acid. Enzymatic Activity of RPE65 (PLACEHOLDER) Figure 2: The canonical Visual Cycle in Humans [1] Protein-Ligand Interaction Endogenous Ligand (PLACEHOLDER) Exogenous Ligand (R)-Emixustat (ACU-4429) spinqualitylabelsall models Figure 3:(R)-emixustat and palmitate bound in the active site of RPE65 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image (R)-emixustat (ACU-4429) is an investigational small molecule inhibitor of RPE65 first invented by a British-American chemist, Ian L. Scott. Formulated as an hydrochloride salt, (R)-emixustat hydrochloride is taken by mouth and functions as a visual cycle modulator (VCM) to reduce toxic retinal byproducts in the canonical visual cycle such as A2E. In 2008, Acucela Inc. partnered with Otsuka Pharmaceutical Company for the continued development of (R)-emixustat as a potential inhibitor of RPE65. Currently (R)-emixustat is in Phase III clinical trials in the United States for the potential treatment of Stargard's disease, a juvenile form of atrophic (dry) age dependent macular degeneration (AMD). Additionally, (R)-emixustat is investigated as potential therapy for diabetic retinopathy and diabetic macular edema. Historically (R)-Emixustat was tested as a possible treatment for dry (atrophic) age-related macular degeneration in Phase IIb/III clinical trials but failed to show clinical outcomes due to significant pharmacokinetic and pharmacodynamic short falls.

(S)-Emixustat

spinqualitylabelsall models Figure 4:(S)-emixustat and palmitate bound in the active site of RPE65 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image (PLACEHOLDER)

R/S Enantiomers Differences

(PLACEHOLDER)

Disease Implications

(PLACEHOLDER)

Medical Relevance

Dry (atrophic) age related macular degeneration

Stargadt's Disease

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References

1. ↑ Shin Y, Moiseyev G, Petrukhin K, Cioffi CL, Muthuraman P, Takahashi Y, Ma JX. A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration. Biochim Biophys Acta Mol Basis Dis. 2018 Jul;1864(7):2420-2429. doi:, 10.1016/j.bbadis.2018.04.014. Epub 2018 Apr 21. PMID:29684583 doi:http://dx.doi.org/10.1016/j.bbadis.2018.04.014