View source for 9xz1


==KRAS(G12C)-RNK07311-HSP90(N-terminus)==
<StructureSection load='9xz1' size='340' side='right'caption='[[9xz1]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9xz1]] is a 2 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=9XZ1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9XZ1 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]] 1.96&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CRY:5-[2,4-bis(oxidanyl)-5-propan-2-yl-phenyl]-4-[4-[[4-[4-[2-[[7-(8-chloranylnaphthalen-1-yl)-4-[(3~{S})-3-(cyanomethyl)-4-propanoyl-piperazin-1-yl]-6,8-dihydro-5~{H}-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethyl]piperazin-1-yl]carbonylpiperidin-1-yl]methyl]phenyl]-1,2,4-triazole-3-carboxamide'>A1CRY</scene>, <scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</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=9xz1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9xz1 OCA], [https://pdbe.org/9xz1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9xz1 RCSB], [https://www.ebi.ac.uk/pdbsum/9xz1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9xz1 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
While KRAS(G12C) inhibitors have shown promising results in clinical activity, acquired resistance remains a significant barrier to durable responses. Combination therapies have been explored to improve the efficacy of KRAS(G12C) inhibitors; however, their use is often restricted due to toxicity and limitations in clinically amenable dosing schedules. Transcriptomic profiling and functional assays on acquired resistant models to adagrasib identified an enrichment of HSP90 client proteins in resistant phenotypes, suggesting a therapeutic vulnerability. To address the finding, RNK07421, a novel heterobifunctional molecule, was developed to simultaneously target KRAS(G12C) and HSP90-client oncoproteins. Structural and biochemical analyses demonstrated that RNK07421 disrupts KRAS(G12C) interactions by inducing a non-natural interface with HSP90, thereby impairing oncogenic signaling. In vitro, RNK07421 effectively suppressed ERK reactivation and reduced viability in KRAS(G12C)-mutant cell lines exhibiting either intrinsic or acquired resistance. In vivo, RNK07421 significantly reduced tumor burden in xenograft models, outperforming both monotherapies and combination therapies. These findings highlight dual KRAS(G12C) and HSP90 inhibition as a promising strategy to overcome resistance in KRAS(G12C)-driven cancers.

Chaperone directed heterobifunctional molecules circumvent KRAS(G12C) inhibitor resistance.,Pulido I, Luan Q, Pastor-Puente S, Gunder L, Wang Y, Ying C, Li J, Sun Y, Dai Y, Ascoli C, Abdelhady K, Massad M, Prince TL, Wang G, Foley KP, Ying W, Papautsky I, Carretero J, Shimamura T Cancer Lett. 2025 Jul 10;622:217691. doi: 10.1016/j.canlet.2025.217691. Epub 2025 , Apr 7. PMID:40204148<ref>PMID:40204148</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9xz1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Foley KP]]
[[Category: Prince TL]]
[[Category: Wang Y]]
[[Category: Ying C]]
[[Category: Ying W]]