8gem: Difference between revisions
New page: '''Unreleased structure''' The entry 8gem is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures |
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==Crystal structure of human cellular retinol binding protein 1 in complex with N-ethyl-N-({3-[1-(4-methylphenyl)cyclopentyl]-1,2,4-oxadiazol-5-yl}methyl)-2-(1H-pyrazol-1-yl)ethanamine== | |||
<StructureSection load='8gem' size='340' side='right'caption='[[8gem]], [[Resolution|resolution]] 1.55Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8gem]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8GEM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GEM 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]] 1.55Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZDF:N-ethyl-N-({3-[1-(4-methylphenyl)cyclopentyl]-1,2,4-oxadiazol-5-yl}methyl)-2-(1H-pyrazol-1-yl)ethan-1-amine'>ZDF</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=8gem FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gem OCA], [https://pdbe.org/8gem PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gem RCSB], [https://www.ebi.ac.uk/pdbsum/8gem PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gem ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/RET1_HUMAN RET1_HUMAN] Intracellular transport of retinol. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The dysregulation of retinoid metabolism has been linked to prevalent ocular diseases including age-related macular degeneration and Stargardt disease. Modulating retinoid metabolism through pharmacological approaches holds promise for the treatment of these eye diseases. Cellular retinol-binding protein 1 (CRBP1) is the primary transporter of all-trans-retinol (atROL) in the eye, and its inhibition has recently been shown to protect mouse retinas from light-induced retinal damage. In this report, we employed high-throughput screening to identify new chemical scaffolds for competitive, nonretinoid inhibitors of CRBP1. To understand the mechanisms of interaction between CRBP1 and these inhibitors, we solved high-resolution X-ray crystal structures of the protein in complex with six selected compounds. By combining protein crystallography with hydrogen/deuterium exchange mass spectrometry, we quantified the conformational changes in CRBP1 caused by different inhibitors and correlated their magnitude with apparent binding affinities. Furthermore, using molecular dynamic simulations, we provided evidence for the functional significance of the "closed" conformation of CRBP1 in retaining ligands within the binding pocket. Collectively, our study outlines the molecular foundations for understanding the mechanism of high-affinity interactions between small molecules and CRBPs, offering a framework for the rational design of improved inhibitors for this class of lipid-binding proteins. | |||
Discovery of Nonretinoid Inhibitors of CRBP1: Structural and Dynamic Insights for Ligand-Binding Mechanisms.,Plau J, Morgan CE, Fedorov Y, Banerjee S, Adams DJ, Blaner WS, Yu EW, Golczak M ACS Chem Biol. 2023 Sep 15. doi: 10.1021/acschembio.3c00402. PMID:37713257<ref>PMID:37713257</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8gem" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Retinol-binding protein 3D structures|Retinol-binding protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Golczak M]] | |||
[[Category: Plau J]] | |||
Latest revision as of 20:45, 1 November 2023
Crystal structure of human cellular retinol binding protein 1 in complex with N-ethyl-N-({3-[1-(4-methylphenyl)cyclopentyl]-1,2,4-oxadiazol-5-yl}methyl)-2-(1H-pyrazol-1-yl)ethanamineCrystal structure of human cellular retinol binding protein 1 in complex with N-ethyl-N-({3-[1-(4-methylphenyl)cyclopentyl]-1,2,4-oxadiazol-5-yl}methyl)-2-(1H-pyrazol-1-yl)ethanamine
Structural highlights
FunctionRET1_HUMAN Intracellular transport of retinol. Publication Abstract from PubMedThe dysregulation of retinoid metabolism has been linked to prevalent ocular diseases including age-related macular degeneration and Stargardt disease. Modulating retinoid metabolism through pharmacological approaches holds promise for the treatment of these eye diseases. Cellular retinol-binding protein 1 (CRBP1) is the primary transporter of all-trans-retinol (atROL) in the eye, and its inhibition has recently been shown to protect mouse retinas from light-induced retinal damage. In this report, we employed high-throughput screening to identify new chemical scaffolds for competitive, nonretinoid inhibitors of CRBP1. To understand the mechanisms of interaction between CRBP1 and these inhibitors, we solved high-resolution X-ray crystal structures of the protein in complex with six selected compounds. By combining protein crystallography with hydrogen/deuterium exchange mass spectrometry, we quantified the conformational changes in CRBP1 caused by different inhibitors and correlated their magnitude with apparent binding affinities. Furthermore, using molecular dynamic simulations, we provided evidence for the functional significance of the "closed" conformation of CRBP1 in retaining ligands within the binding pocket. Collectively, our study outlines the molecular foundations for understanding the mechanism of high-affinity interactions between small molecules and CRBPs, offering a framework for the rational design of improved inhibitors for this class of lipid-binding proteins. Discovery of Nonretinoid Inhibitors of CRBP1: Structural and Dynamic Insights for Ligand-Binding Mechanisms.,Plau J, Morgan CE, Fedorov Y, Banerjee S, Adams DJ, Blaner WS, Yu EW, Golczak M ACS Chem Biol. 2023 Sep 15. doi: 10.1021/acschembio.3c00402. PMID:37713257[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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