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| | <StructureSection load='7lmw' size='340' side='right'caption='[[7lmw]], [[Resolution|resolution]] 2.50Å' scene=''> | | <StructureSection load='7lmw' size='340' side='right'caption='[[7lmw]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7lmw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LMW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LMW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7lmw]] is a 2 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=7LMW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LMW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=Y6P:7-methyl-3-(1~{H}-pyrazol-4-yl)-1~{H}-indole-2-carboxylic+acid'>Y6P</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]] 2.5Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6xq1|6xq1]], [[6xq3|6xq3]], [[6xq5|6xq5]], [[6xq6|6xq6]], [[6xq7|6xq7]], [[6xq8|6xq8]], [[6xq9|6xq9]], [[7lml|7lml]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=Y6P:7-methyl-3-(1~{H}-pyrazol-4-yl)-1~{H}-indole-2-carboxylic+acid'>Y6P</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AGER, RAGE ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=7lmw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lmw OCA], [https://pdbe.org/7lmw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lmw RCSB], [https://www.ebi.ac.uk/pdbsum/7lmw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lmw 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=7lmw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lmw OCA], [https://pdbe.org/7lmw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lmw RCSB], [https://www.ebi.ac.uk/pdbsum/7lmw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lmw ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/RAGE_HUMAN RAGE_HUMAN]] Mediates interactions of advanced glycosylation end products (AGE). These are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. Acts as a mediator of both acute and chronic vascular inflammation in conditions such as atherosclerosis and in particular as a complication of diabetes. AGE/RAGE signaling plays an important role in regulating the production/expression of TNF-alpha, oxidative stress, and endothelial dysfunction in type 2 diabetes. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Receptor for amyloid beta peptide. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space.<ref>PMID:19906677</ref>
| + | [https://www.uniprot.org/uniprot/RAGE_HUMAN RAGE_HUMAN] Mediates interactions of advanced glycosylation end products (AGE). These are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. Acts as a mediator of both acute and chronic vascular inflammation in conditions such as atherosclerosis and in particular as a complication of diabetes. AGE/RAGE signaling plays an important role in regulating the production/expression of TNF-alpha, oxidative stress, and endothelial dysfunction in type 2 diabetes. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Receptor for amyloid beta peptide. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space.<ref>PMID:19906677</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chazin, W J]] | + | [[Category: Chazin WJ]] |
| - | [[Category: Christov, P P]] | + | [[Category: Christov PP]] |
| - | [[Category: Gilston, B A]] | + | [[Category: Gilston BA]] |
| - | [[Category: Gogliotti, R D]] | + | [[Category: Gogliotti RD]] |
| - | [[Category: Kim, K]] | + | [[Category: Kim K]] |
| - | [[Category: Kozlyuk, N]] | + | [[Category: Kozlyuk N]] |
| - | [[Category: Ovee, M]] | + | [[Category: Ovee M]] |
| - | [[Category: Salay, L E]] | + | [[Category: Salay LE]] |
| - | [[Category: Waterson, A G]] | + | [[Category: Waterson AG]] |
| - | [[Category: Advanced glycation end product]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Rage]]
| + | |
| - | [[Category: Receptor]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Function
RAGE_HUMAN Mediates interactions of advanced glycosylation end products (AGE). These are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. Acts as a mediator of both acute and chronic vascular inflammation in conditions such as atherosclerosis and in particular as a complication of diabetes. AGE/RAGE signaling plays an important role in regulating the production/expression of TNF-alpha, oxidative stress, and endothelial dysfunction in type 2 diabetes. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Receptor for amyloid beta peptide. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space.[1]
Publication Abstract from PubMed
The Receptor for Advanced Glycation End products (RAGE) is a pattern recognition receptor that signals for inflammation via the NF-kappaB pathway. RAGE has been pursued as a potential target to suppress symptoms of diabetes and is of interest in a number of other diseases associated with chronic inflammation, such as inflammatory bowel disease and bronchopulmonary dysplasia. Screening and optimization have previously produced small molecules that inhibit the activity of RAGE in cell-based assays, but efforts to develop a therapeutically viable direct-binding RAGE inhibitor have yet to be successful. Here, we show that a fragment-based approach can be applied to discover fundamentally new types of RAGE inhibitors that specifically target the ligand-binding surface. A series of systematic assays of structural stability, solubility, and crystallization were performed to select constructs of the RAGE ligand-binding domain and optimize conditions for NMR-based screening and co-crystallization of RAGE with hit fragments. An NMR-based screen of a highly curated ~14 000-member fragment library produced 21 fragment leads. Of these, three were selected for elaboration based on structure-activity relationships generated through cycles of structural analysis by X-ray crystallography, structure-guided design principles, and synthetic chemistry. These results, combined with crystal structures of the first linked fragment compounds, demonstrate the applicability of the fragment-based approach to the discovery of RAGE inhibitors.
A fragment-based approach to discovery of Receptor for Advanced Glycation End products inhibitors.,Kozlyuk N, Gilston BA, Salay LE, Gogliotti RD, Christov PP, Kim K, Ovee M, Waterson AG, Chazin WJ Proteins. 2021 Jun 22. doi: 10.1002/prot.26162. PMID:34156100[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Fang F, Lue LF, Yan S, Xu H, Luddy JS, Chen D, Walker DG, Stern DM, Yan S, Schmidt AM, Chen JX, Yan SS. RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB J. 2010 Apr;24(4):1043-55. doi: 10.1096/fj.09-139634. Epub 2009 Nov 11. PMID:19906677 doi:10.1096/fj.09-139634
- ↑ Kozlyuk N, Gilston BA, Salay LE, Gogliotti RD, Christov PP, Kim K, Ovee M, Waterson AG, Chazin WJ. A fragment-based approach to discovery of Receptor for Advanced Glycation End products inhibitors. Proteins. 2021 Jun 22. doi: 10.1002/prot.26162. PMID:34156100 doi:http://dx.doi.org/10.1002/prot.26162
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