8doc: Difference between revisions
New page: '''Unreleased structure''' The entry 8doc is ON HOLD Authors: Bassetto, M., Kiser, P.D. Description: Crystal structure of RPE65 in complex with MB-003 and palmitate [[Category: Unrelea... |
No edit summary |
||
| (5 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Crystal structure of RPE65 in complex with compound 16e and palmitate== | ||
<StructureSection load='8doc' size='340' side='right'caption='[[8doc]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8doc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DOC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DOC FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CXS:3-CYCLOHEXYL-1-PROPYLSULFONIC+ACID'>CXS</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=SYL:(1R)-1-[3-(cyclohexylmethoxy)phenyl]-3-(methylamino)propan-1-ol'>SYL</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8doc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8doc OCA], [https://pdbe.org/8doc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8doc RCSB], [https://www.ebi.ac.uk/pdbsum/8doc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8doc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/RPE65_BOVIN RPE65_BOVIN] Plays important roles in the production of 11-cis retinal and in visual pigment regeneration. The soluble form binds vitamin A (all-trans-retinol), making it available for LRAT processing to all-trans-retinyl ester. The membrane form, palmitoylated by LRAT, binds all-trans-retinyl esters, making them available for IMH (isomerohydrolase) processing to all-cis-retinol. The soluble form is regenerated by transferring its palmitoyl groups onto 11-cis-retinol, a reaction catalyzed by LRAT. The enzymatic activity is linearly dependent of the expression levels and membrane association.<ref>PMID:16096063</ref> <ref>PMID:19805034</ref> <ref>PMID:20100834</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In the eye, the isomerization of all-trans-retinal to 11-cis-retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essential trans-cis 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 gamma-amino-alpha-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 in vitro and in vivo 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. | |||
Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif.,Bassetto M, Zaluski J, Li B, Zhang J, Badiee M, Kiser PD, Tochtrop GP J Med Chem. 2023 Jun 22;66(12):8140-8158. doi: 10.1021/acs.jmedchem.3c00461. Epub , 2023 Jun 6. PMID:37279401<ref>PMID:37279401</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Bassetto | <div class="pdbe-citations 8doc" style="background-color:#fffaf0;"></div> | ||
[[Category: Kiser | |||
==See Also== | |||
*[[Retinoid isomerohydrolase|Retinoid isomerohydrolase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bos taurus]] | |||
[[Category: Large Structures]] | |||
[[Category: Bassetto M]] | |||
[[Category: Kiser PD]] | |||