8DOC
Crystal structure of RPE65 in complex with compound 16e and palmitate
Summary for 8DOC
| Entry DOI | 10.2210/pdb8doc/pdb |
| Descriptor | Retinoid isomerohydrolase, FE (II) ION, 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID, ... (6 entities in total) |
| Functional Keywords | 7-bladed beta propeller, monotopic membrane protein, non-heme iron enzyme, retinoid isomerase, inhibitor, complex, hydrolase |
| Biological source | Bos taurus (cattle) |
| Total number of polymer chains | 1 |
| Total formula weight | 61746.03 |
| Authors | Bassetto, M.,Kiser, P.D. (deposition date: 2022-07-12, release date: 2023-05-24, Last modification date: 2024-11-06) |
| Primary citation | Bassetto, M.,Zaluski, J.,Li, B.,Zhang, J.,Badiee, M.,Kiser, P.D.,Tochtrop, G.P. Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif. J.Med.Chem., 66:8140-8158, 2023 Cited by PubMed Abstract: In the eye, the isomerization of all--retinal to 11--retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essential - isomerase of this pathway. Emixustat, a retinoid-mimetic RPE65 inhibitor, was developed as a therapeutic visual cycle modulator and used for the treatment of retinopathies. However, pharmacokinetic liabilities limit its further development including: (1) metabolic deamination of the γ-amino-α-aryl alcohol, which mediates targeted RPE65 inhibition, and (2) unwanted long-lasting RPE65 inhibition. We sought to address these issues by more broadly defining the structure-activity relationships of the RPE65 recognition motif via the synthesis of a family of novel derivatives, which were tested and for RPE65 inhibition. We identified a potent secondary amine derivative with resistance to deamination and preserved RPE65 inhibitory activity. Our data provide insights into activity-preserving modifications of the emixustat molecule that can be employed to tune its pharmacological properties. PubMed: 37279401DOI: 10.1021/acs.jmedchem.3c00461 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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