|
|
| Line 4: |
Line 4: |
| | == Structural highlights == | | == Structural highlights == |
| | <table><tr><td colspan='2'>[[4zhk]] 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=4ZHK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZHK FirstGlance]. <br> | | <table><tr><td colspan='2'>[[4zhk]] 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=4ZHK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZHK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A8V:(1S)-1-[3-(CYCLOHEXYLMETHOXY)PHENYL]PROPANE-1,3-DIOL'>A8V</scene>, <scene name='pdbligand=A9V:(1R)-1-[3-(CYCLOHEXYLMETHOXY)PHENYL]PROPANE-1,3-DIOL'>A9V</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A8V:(1S)-1-[3-(CYCLOHEXYLMETHOXY)PHENYL]PROPANE-1,3-DIOL'>A8V</scene>, <scene name='pdbligand=A9V:(1R)-1-[3-(CYCLOHEXYLMETHOXY)PHENYL]PROPANE-1,3-DIOL'>A9V</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Retinoid_isomerohydrolase Retinoid isomerohydrolase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.64 3.1.1.64] </span></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=4zhk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zhk OCA], [https://pdbe.org/4zhk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zhk RCSB], [https://www.ebi.ac.uk/pdbsum/4zhk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zhk ProSAT]</span></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=4zhk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zhk OCA], [https://pdbe.org/4zhk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zhk RCSB], [https://www.ebi.ac.uk/pdbsum/4zhk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zhk ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == 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>
| + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 29: |
Line 27: |
| | [[Category: Bos taurus]] | | [[Category: Bos taurus]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Retinoid isomerohydrolase]]
| + | [[Category: Kiser PD]] |
| - | [[Category: Kiser, P D]] | + | [[Category: Palczewski K]] |
| - | [[Category: Palczewski, K]] | + | |
| - | [[Category: 7-bladed beta propeller]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Isomerase]]
| + | |
| - | [[Category: Monotopic membrane protein]]
| + | |
| - | [[Category: Non-heme iron protein]]
| + | |
| - | [[Category: Retinoid isomerase]]
| + | |
| - | [[Category: Smooth endoplasmic reticulum]]
| + | |
| Structural highlights
4zhk 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.
| | 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
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[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Zhang J, Kiser PD, Badiee M, Palczewska G, Dong Z, Golczak M, Tochtrop GP, Palczewski K. Molecular pharmacodynamics of emixustat in protection against retinal degeneration. J Clin Invest. 2015 Jul 1;125(7):2781-94. doi: 10.1172/JCI80950. Epub 2015 Jun, 15. PMID:26075817 doi:http://dx.doi.org/10.1172/JCI80950
|
