8fjh

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of RalA in a covalent complex with SOF-531

Structural highlights

8fjh is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.54Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

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^[4]

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

References

↑ Cascone I, Selimoglu R, Ozdemir C, Del Nery E, Yeaman C, White M, Camonis J. Distinct roles of RalA and RalB in the progression of cytokinesis are supported by distinct RalGEFs. EMBO J. 2008 Sep 17;27(18):2375-87. doi: 10.1038/emboj.2008.166. Epub 2008 Aug, 28. PMID:18756269 doi:http://dx.doi.org/10.1038/emboj.2008.166
↑ Aziziyeh AI, Li TT, Pape C, Pampillo M, Chidiac P, Possmayer F, Babwah AV, Bhattacharya M. Dual regulation of lysophosphatidic acid (LPA1) receptor signalling by Ral and GRK. Cell Signal. 2009 Jul;21(7):1207-17. doi: 10.1016/j.cellsig.2009.03.011. Epub, 2009 Mar 21. PMID:19306925 doi:10.1016/j.cellsig.2009.03.011
↑ Balasubramanian N, Meier JA, Scott DW, Norambuena A, White MA, Schwartz MA. RalA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling. Curr Biol. 2010 Jan 12;20(1):75-9. doi: 10.1016/j.cub.2009.11.016. Epub 2009 Dec , 10. PMID:20005108 doi:http://dx.doi.org/10.1016/j.cub.2009.11.016
↑ Landgraf AD, Yeh IJ, Ghozayel MK, Bum-Erdene K, Gonzalez-Gutierrez G, Meroueh SO. Exploring Covalent Bond Formation at Tyr-82 for Inhibition of Ral GTPase Activation. ChemMedChem. 2023 Aug 15;18(16):e202300272. PMID:37269475 doi:10.1002/cmdc.202300272

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8fjh"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[8fjh]] 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=8FJH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FJH 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]] 1.54&#8491;</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=Y0P:8-[bis(oxidanyl)-$l^{3}-sulfanyl]-~{N}-(3-fluoranyl-5-methoxy-phenyl)-2,3-dihydro-1,4-benzodioxine-5-sulfonamide'>Y0P</scene></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=Y0P:8-[(3-fluoranyl-5-methoxy-phenyl)sulfamoyl]-2,3-dihydro-1,4-benzodioxine-5-sulfonyl+fluoride'>Y0P</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=8fjh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fjh OCA], [https://pdbe.org/8fjh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fjh RCSB], [https://www.ebi.ac.uk/pdbsum/8fjh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fjh ProSAT]</span></td></tr>
 </table>

8fjh

From Proteopedia

Current revision

Crystal structure of RalA in a covalent complex with SOF-531

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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