6gj5: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
<StructureSection load='6gj5' size='340' side='right'caption='[[6gj5]], [[Resolution|resolution]] 1.50Å' scene=''> | <StructureSection load='6gj5' size='340' side='right'caption='[[6gj5]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6gj5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GJ5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GJ5 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6gj5]] is a 2 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=6GJ5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GJ5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F0N:(3~{S})-3-[2-[(2~{R})-pyrrolidin-2-yl]-1~{H}-indol-3-yl]-2,3-dihydroisoindol-1-one'>F0N</scene>, <scene name='pdbligand=GCP:PHOSPHOMETHYLPHOSPHONIC+ACID+GUANYLATE+ESTER'>GCP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F0N:(3~{S})-3-[2-[(2~{R})-pyrrolidin-2-yl]-1~{H}-indol-3-yl]-2,3-dihydroisoindol-1-one'>F0N</scene>, <scene name='pdbligand=GCP:PHOSPHOMETHYLPHOSPHONIC+ACID+GUANYLATE+ESTER'>GCP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KRAS, KRAS2, RASK2 ([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=6gj5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gj5 OCA], [http://pdbe.org/6gj5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gj5 RCSB], [http://www.ebi.ac.uk/pdbsum/6gj5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gj5 ProSAT]</span></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=6gj5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gj5 OCA], [http://pdbe.org/6gj5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gj5 RCSB], [http://www.ebi.ac.uk/pdbsum/6gj5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gj5 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| Line 11: | Line 12: | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN]] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. | [[http://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN]] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be "undruggable," between switch I and II on RAS; 1 is mechanistically distinct from covalent KRAS(G12C) inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS. | |||
Drugging an undruggable pocket on KRAS.,Kessler D, Gmachl M, Mantoulidis A, Martin LJ, Zoephel A, Mayer M, Gollner A, Covini D, Fischer S, Gerstberger T, Gmaschitz T, Goodwin C, Greb P, Haring D, Hela W, Hoffmann J, Karolyi-Oezguer J, Knesl P, Kornigg S, Koegl M, Kousek R, Lamarre L, Moser F, Munico-Martinez S, Peinsipp C, Phan J, Rinnenthal J, Sai J, Salamon C, Scherbantin Y, Schipany K, Schnitzer R, Schrenk A, Sharps B, Siszler G, Sun Q, Waterson A, Wolkerstorfer B, Zeeb M, Pearson M, Fesik SW, McConnell DB Proc Natl Acad Sci U S A. 2019 Jul 22. pii: 1904529116. doi:, 10.1073/pnas.1904529116. PMID:31332011<ref>PMID:31332011</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6gj5" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Kessler, D]] | [[Category: Kessler, D]] | ||