View source for 4ryx


==Crystal structure of RPE65 in complex with emixustat and palmitate, P6522 crystal form==
<StructureSection load='4ryx' size='340' side='right'caption='[[4ryx]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ryx]] 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=4RYX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RYX 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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A3V:(1R)-3-AMINO-1-[3-(CYCLOHEXYLMETHOXY)PHENYL]PROPAN-1-OL'>A3V</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4ryx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ryx OCA], [https://pdbe.org/4ryx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ryx RCSB], [https://www.ebi.ac.uk/pdbsum/4ryx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ryx 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 ==
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.

Molecular pharmacodynamics of emixustat in protection against retinal degeneration.,Zhang J, Kiser PD, Badiee M, Palczewska G, Dong Z, Golczak M, Tochtrop GP, Palczewski K J Clin Invest. 2015 Jul 1;125(7):2781-94. doi: 10.1172/JCI80950. Epub 2015 Jun, 15. PMID:26075817<ref>PMID:26075817</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ryx" style="background-color:#fffaf0;"></div>

==See Also==
*[[Retinoid isomerohydrolase|Retinoid isomerohydrolase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Large Structures]]
[[Category: Kiser PD]]
[[Category: Palczewski K]]