9GTK

KRAS in complex with DARPin 784_F5

Summary for 9GTK

• Entry DOI: 10.2210/pdb9gtk/pdb
• Descriptor: Isoform 2B of GTPase KRas, DARPin 784_F5, 1,2-ETHANEDIOL, ... (9 entities in total)
• Functional Keywords: small gtpase, designed ankyrin repeat protein, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 125750.75

Authors

Kapp, J.N.,Verdurmen, W.,Schaefer, J.V.,Kopra, K.,Nagy-Davidescu, G.,Richard, E.,Nokin, M.J.,Ernst, P.,Tamaskovic, R.,Schwill, M.,Degen, R.,Scholl, C.,Santamaria, D.,Plueckthun, A. (deposition date: 2024-09-18, release date: 2025-06-25)

Primary citation

Kapp, J.N.,Verdurmen, W.P.R.,Schaefer, J.V.,Kopra, K.,Nagy-Davidescu, G.,Richard, E.,Nokin, M.J.,Ernst, P.,Tamaskovic, R.,Schwill, M.,Degen, R.,Scholl, C.,Santamaria, D.,Pluckthun, A.
A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.
Mol Oncol, 2025

PubMed Abstract: The KRAS oncoprotein is a frequent tumor driver in lung, pancreatic, and colorectal cancers and has proven to be a challenging pharmaceutical target. The first KRAS-targeted therapeutics are now being tested in clinical trials but the consequences of preferentially targeting the GDP or GTP state of KRAS and the relevance of RAS nanoclustering have remained unclear. Here we report a Designed Ankyrin Repeat Protein (DARPin) that recognizes the RAS switch I/II region with low nm affinity, independently of the nucleotide bound (GDP- or GTP state). This DARPin, termed '784_F5', occupies the effector recognition lobe, resulting in interference with SOS-mediated activation, RAS downstream effector interactions, and KRAS nanoclustering. Consequently, this anti-RAS DARPin potently blocks downstream signaling, leading to a strong reduction in proliferation and anchorage-independent growth in RAS-dependent cell lines. We showed that the expression of '784_F5', the pan-RAS, nucleotide-independent DARPin can lead to tumor regression in a colorectal xenograft model which may hold promise for further investigation and development.

PubMed: 40517320
DOI: 10.1002/1878-0261.70061

Experimental method

X-RAY DIFFRACTION (2 Å)