8fji
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of RalA in a covalent complex with SOF-367== | |
| + | <StructureSection load='8fji' size='340' side='right'caption='[[8fji]], [[Resolution|resolution]] 1.48Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8fji]] 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=8FJI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FJI 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]] 1.48Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=Y0M:8-[(2-methoxypyridin-3-yl)sulfamoyl]-2,3-dihydro-1,4-benzodioxine-5-sulfonyl+fluoride'>Y0M</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=8fji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fji OCA], [https://pdbe.org/8fji PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fji RCSB], [https://www.ebi.ac.uk/pdbsum/8fji PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fji ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/RALA_HUMAN RALA_HUMAN] Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking. Accomplishes its multiple functions by interacting with distinct downstream effectors. Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles. Plays a role in the early stages of cytokinesis and is required to tether the exocyst to the cytokinetic furrow. The RALA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling. Key regulator of LPAR1 signaling and competes with ADRBK1 for binding to LPAR1 thus affecting the signaling properties of the receptor. Required for anchorage-independent proliferation of transformed cells.<ref>PMID:18756269</ref> <ref>PMID:19306925</ref> <ref>PMID:20005108</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Ral RAS GTPases are directly activated by KRAS through a trimeric complex with a guanine exchange factor. Ral is considered undruggable and lacks an accessible cysteine for covalent drug development. Previously we had reported an aryl sulfonyl fluoride fragment that formed a covalent bond at Tyr-82 on Ral and created a deep and well-defined pocket. Here, we explore this pocket further through design and synthesis of several fragment derivatives. The fragment core is modified by introducing tetrahydronaphthalene or benzodioxane rings to enhance affinity and stability of the sulfonyl fluoride reactive group. The deep pocket in the Switch II region is also explored by modifying the aromatic ring of the fragment that is ensconced into the pocket. Compounds 19 (SOF-658) and 26 (SOF-648) formed a single robust adduct specifically at Tyr-82, inhibited Ral GTPase exchange in buffer and in mammalian cells, and blocked invasion of pancreatic ductal adenocarcinoma cancer cells. Compound 19 (SOF-658) was stable in buffer, mouse, and human microsomes suggesting that further optimization could lead to small molecules to probe Ral activity in tumor models. | ||
| - | + | Exploring Covalent Bond Formation at Tyr-82 for Inhibition of Ral GTPase Activation.,Landgraf AD, Yeh IJ, Ghozayel MK, Bum-Erdene K, Gonzalez-Gutierrez G, Meroueh SO ChemMedChem. 2023 Aug 15;18(16):e202300272. doi: 10.1002/cmdc.202300272. Epub , 2023 Jul 6. PMID:37269475<ref>PMID:37269475</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8fji" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Bum-Erdene K]] | ||
| + | [[Category: Gonzalez-Gutierrez G]] | ||
| + | [[Category: Landgraf AD]] | ||
| + | [[Category: Meroueh S]] | ||
| + | [[Category: Yeh I-J]] | ||
Current revision
Crystal structure of RalA in a covalent complex with SOF-367
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