View source for 9glz


==KRas-G12D-GMPPnP in complex with the nanobody KM12-AM==
<StructureSection load='9glz' size='340' side='right'caption='[[9glz]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9glz]] is a 4 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=9GLZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9GLZ 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]] 2.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=9glz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9glz OCA], [https://pdbe.org/9glz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9glz RCSB], [https://www.ebi.ac.uk/pdbsum/9glz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9glz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A7K5XXT4_9CHAR A0A7K5XXT4_9CHAR] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
RAS proteins control cell proliferation and activating mutations are collectively the most frequent oncogenic event observed in cancer patients, justifying investments into multiple drug discovery efforts. While RAS-directed therapeutic agents targeting either the inactive GDP-bound or the active GTP-bound state have entered the clinic, invariably resistance is observed. Mutations at drug binding sites represent a common resistance mechanism indicating the need to discover new targetable pockets in RAS. Such efforts are hindered by the small globular size of the protein, for long considered undruggable. Here we perform macrocyclic peptides mRNA and nanobody yeast display screens and discover a targetable ligand-induced pocket in RAS. In vitro and cellular experiments with the KM12 and KM12-AM nanobodies show RAS inhibition via displacement of cRAF, by affecting their protein-protein interaction via the less studied cRAF CRD domain. Further, we provide orthogonal functional validation for the discovered binding pocket via mutagenesis experiments. Notably, the discovered RAS-targeting approach enables simultaneous targeting of both GTP-bound active and GDP-bound inactive states and leaves the SwII pocket unaltered, opening possibilities of combinatorial approaches with clinically approved SwII pocket inhibitors.

Identification and characterization of binders to a cryptic and functional pocket in KRAS.,Beyer KS, Klein J, Katz S, Welker P, Lanter M, Guthy D, Pollehn K, Gluck-Gade A, Bleu M, Desogus J, Hattenberger M, Borrello D, Abdul Rahman W, Zink F, Ostermann N, Jahnke W, Dumelin CE, Leder L, Esser O, Muller L, Marzinzik A, Cebe R, Muller K, Galli GG, Tordella L, Cotesta S, Brachmann SM, Maira SM Nat Commun. 2025 Dec 2;16(1):10836. doi: 10.1038/s41467-025-65844-3. PMID:41330964<ref>PMID:41330964</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9glz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ostermann N]]
[[Category: Zink F]]