6p0j: Difference between revisions

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== Structural highlights ==

<table><tr><td colspan='2'>[[6p0j]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P0J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P0J FirstGlance]. <br>

<table><tr><td colspan='2'>[[6p0j]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P0J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P0J FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene></td></tr>

<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RALA, RAL ([http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6p0j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p0j OCA], [http://pdbe.org/6p0j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p0j RCSB], [http://www.ebi.ac.uk/pdbsum/6p0j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p0j ProSAT]</span></td></tr>

</table>

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== Publication Abstract from PubMed ==

~~Macromolecular X~~-~~ray crystallography is routinely applied to understand biological processes at a molecular level~~. However, ~~significant time~~ and ~~effort~~ are ~~still required to solve~~ and ~~complete many of these structures because of~~ the ~~need for manual interpretation~~ of ~~complex numerical data using many software packages and the repeated use~~ of ~~interactive three~~-~~dimensional graphics~~. ~~PHENIX has been developed~~ to ~~provide~~ a ~~comprehensive system for macromolecular crystallographic~~ structure ~~solution~~ with ~~an emphasis on~~ the ~~automation~~ of ~~all procedures~~. ~~This has relied~~ on ~~the development~~ of ~~algorithms~~ that ~~minimize or eliminate subjective input, the development of algorithms that automate procedures~~ that are ~~traditionally performed by hand and, finally, the development~~ of a ~~framework that allows a tight integration between the algorithms~~.

Ral (Ras-like) GTPases are directly activated by oncogenic Ras GTPases. Mutant K-Ras (G12C) has enabled the development of covalent K-Ras inhibitors currently in clinical trials. However, Ral, and the overwhelming majority of mutant oncogenic K-Ras, are devoid of a druggable pocket and lack an accessible cysteine for the development of a covalent inhibitor. Here, we report that covalent bond formation by an aryl sulfonyl fluoride electrophile at a tyrosine residue (Tyr-82) inhibits guanine exchange factor Rgl2-mediated nucleotide exchange of Ral GTPase. A high-resolution 1.18-A X-ray cocrystal structure shows that the compound binds to a well-defined binding site in RalA as a result of a switch II loop conformational change. The structure, along with additional high-resolution crystal structures of several analogs in complex with RalA, confirm the importance of key hydrogen bond anchors between compound sulfone oxygen atoms and Ral backbone nitrogen atoms. Our discovery of a pocket with features found on known druggable sites and covalent modification of a bystander tyrosine residue present in Ral and Ras GTPases provide a strategy that could lead to therapeutic agent targeting oncogenic Ras mutants that are devoid of a cysteine nucleophile.

~~PHENIX:~~ a ~~comprehensive Python-based system for macromolecular structure solution~~.,~~Adams PD~~, ~~Afonine PV~~, ~~Bunkoczi~~ G, ~~Chen VB~~, ~~Davis IW~~, ~~Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW, McCoy AJ, Moriarty NW, Oeffner R, Read RJ, Richardson DC, Richardson JS, Terwilliger TC, Zwart PH Acta Crystallogr D Biol Crystallogr~~. ~~2010 Feb;66(Pt 2)~~:~~213-21~~. ~~Epub 2010~~, ~~Jan 22~~. PMID:~~20124702~~<ref>PMID:~~20124702~~</ref>

Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases.,Bum-Erdene K, Liu D, Gonzalez-Gutierrez G, Ghozayel MK, Xu D, Meroueh SO Proc Natl Acad Sci U S A. 2020 Mar 16. pii: 1913654117. doi:, 10.1073/pnas.1913654117. PMID:32179690<ref>PMID:32179690</ref>

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

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__TOC__

</StructureSection>

[[Category: Human]]

[[Category: Large Structures]]

[[Category: Bum-Erdene, K]]

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 <StructureSection load='6p0j' size='340' side='right'caption='[[6p0j]], [[Resolution|resolution]] 1.31&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6p0j]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P0J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P0J FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6p0j]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P0J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P0J FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RALA, RAL ([http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6p0j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p0j OCA], [http://pdbe.org/6p0j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p0j RCSB], [http://www.ebi.ac.uk/pdbsum/6p0j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p0j ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 12: @@
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-Macromolecular X-ray crystallography is routinely applied to understand biological processes at a molecular level. However, significant time and effort are still required to solve and complete many of these structures because of the need for manual interpretation of complex numerical data using many software packages and the repeated use of interactive three-dimensional graphics. PHENIX has been developed to provide a comprehensive system for macromolecular crystallographic structure solution with an emphasis on the automation of all procedures. This has relied on the development of algorithms that minimize or eliminate subjective input, the development of algorithms that automate procedures that are traditionally performed by hand and, finally, the development of a framework that allows a tight integration between the algorithms.
+Ral (Ras-like) GTPases are directly activated by oncogenic Ras GTPases. Mutant K-Ras (G12C) has enabled the development of covalent K-Ras inhibitors currently in clinical trials. However, Ral, and the overwhelming majority of mutant oncogenic K-Ras, are devoid of a druggable pocket and lack an accessible cysteine for the development of a covalent inhibitor. Here, we report that covalent bond formation by an aryl sulfonyl fluoride electrophile at a tyrosine residue (Tyr-82) inhibits guanine exchange factor Rgl2-mediated nucleotide exchange of Ral GTPase. A high-resolution 1.18-A X-ray cocrystal structure shows that the compound binds to a well-defined binding site in RalA as a result of a switch II loop conformational change. The structure, along with additional high-resolution crystal structures of several analogs in complex with RalA, confirm the importance of key hydrogen bond anchors between compound sulfone oxygen atoms and Ral backbone nitrogen atoms. Our discovery of a pocket with features found on known druggable sites and covalent modification of a bystander tyrosine residue present in Ral and Ras GTPases provide a strategy that could lead to therapeutic agent targeting oncogenic Ras mutants that are devoid of a cysteine nucleophile.
-PHENIX: a comprehensive Python-based system for macromolecular structure solution.,Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW, McCoy AJ, Moriarty NW, Oeffner R, Read RJ, Richardson DC, Richardson JS, Terwilliger TC, Zwart PH Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. Epub 2010, Jan 22. PMID:20124702<ref>PMID:20124702</ref>
+Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases.,Bum-Erdene K, Liu D, Gonzalez-Gutierrez G, Ghozayel MK, Xu D, Meroueh SO Proc Natl Acad Sci U S A. 2020 Mar 16. pii: 1913654117. doi:, 10.1073/pnas.1913654117. PMID:32179690<ref>PMID:32179690</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Bum-Erdene, K]]