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4rsc

From Proteopedia

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Crystal structure of RPE65 in complex with emixustat and palmitate

Structural highlights

4rsc is a 2 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Visual function in vertebrates is dependent on the membrane-bound retinoid isomerase RPE65, an essential component of the retinoid cycle pathway that regenerates 11-cis-retinal for rod and cone opsins. The mechanism by which RPE65 catalyzes stereoselective retinoid isomerization has remained elusive because of uncertainty about how retinoids bind to its active site. Here we present crystal structures of RPE65 in complex with retinoid-mimetic compounds, one of which is in clinical trials for the treatment of age-related macular degeneration. The structures reveal the active site retinoid-binding cavity located near the membrane-interacting surface of the enzyme as well as an Fe-bound palmitate ligand positioned in an adjacent pocket. With the geometry of the RPE65-substrate complex clarified, we delineate a mechanism of catalysis that reconciles the extensive biochemical and structural research on this enzyme. These data provide molecular foundations for understanding a key process in vision and pharmacological inhibition of RPE65 with small molecules.

Catalytic mechanism of a retinoid isomerase essential for vertebrate vision.,Kiser PD, Zhang J, Badiee M, Li Q, Shi W, Sui X, Golczak M, Tochtrop GP, Palczewski K Nat Chem Biol. 2015 Jun;11(6):409-15. doi: 10.1038/nchembio.1799. Epub 2015 Apr, 20. PMID:25894083^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Jin M, Li S, Moghrabi WN, Sun H, Travis GH. Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell. 2005 Aug 12;122(3):449-59. PMID:16096063 doi:10.1016/j.cell.2005.06.042
↑ Kiser PD, Golczak M, Lodowski DT, Chance MR, Palczewski K. Crystal structure of native RPE65, the retinoid isomerase of the visual cycle. Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17325-30. Epub 2009 Oct 5. PMID:19805034
↑ Golczak M, Kiser PD, Lodowski DT, Maeda A, Palczewski K. Importance of membrane structural integrity for RPE65 retinoid isomerization activity. J Biol Chem. 2010 Mar 26;285(13):9667-82. Epub 2010 Jan 25. PMID:20100834 doi:10.1074/jbc.M109.063941
↑ Kiser PD, Zhang J, Badiee M, Li Q, Shi W, Sui X, Golczak M, Tochtrop GP, Palczewski K. Catalytic mechanism of a retinoid isomerase essential for vertebrate vision. Nat Chem Biol. 2015 Jun;11(6):409-15. doi: 10.1038/nchembio.1799. Epub 2015 Apr, 20. PMID:25894083 doi:http://dx.doi.org/10.1038/nchembio.1799

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4rsc"

Categories: Bos taurus | Large Structures | Kiser PD | Palczewski K | Shi W

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4rsc]] is a 2 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=4RSC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RSC FirstGlance]. <br>
-</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=PLM:PALMITIC+ACID'>PLM</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#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=PLM:PALMITIC+ACID'>PLM</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=4rsc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rsc OCA], [https://pdbe.org/4rsc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rsc RCSB], [https://www.ebi.ac.uk/pdbsum/4rsc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rsc ProSAT]</span></td></tr>
 </table>

4rsc

From Proteopedia

Current revision

Crystal structure of RPE65 in complex with emixustat and palmitate

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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