9GTK | pdb_00009gtk

KRAS in complex with DARPin 784_F5


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 
    0.201 (Depositor), 0.209 (DCC) 
  • R-Value Work: 
    0.171 (Depositor), 0.182 (DCC) 
  • R-Value Observed: 
    0.172 (Depositor) 

Starting Models: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.

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.

(2025) Mol Oncol 

  • DOI: https://doi.org/10.1002/1878-0261.70061
  • Primary Citation of Related Structures:  
    9GTK

  • 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.


  • Organizational Affiliation

    Department of Biochemistry, University of Zurich, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Isoform 2B of GTPase KRas
A, C, D
195Homo sapiensMutation(s): 0 
Gene Names: KRASKRAS2RASK2
EC: 3.6.5.2
UniProt & NIH Common Fund Data Resources
Find proteins for P01116 (Homo sapiens)
Explore P01116 
Go to UniProtKB:  P01116
PHAROS:  P01116
GTEx:  ENSG00000133703 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01116
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
DARPin 784_F5B,
E [auth H],
F [auth I]
170synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GNP (Subject of Investigation/LOI)
Query on GNP

Download Ideal Coordinates CCD File 
NA [auth C],
T [auth A],
TA [auth D]
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
C10 H17 N6 O13 P3
UQABYHGXWYXDTK-UUOKFMHZSA-N
1PE
Query on 1PE

Download Ideal Coordinates CCD File 
BA [auth B]PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
PGE
Query on PGE

Download Ideal Coordinates CCD File 
CA [auth B],
OA [auth C],
UA [auth D],
WA [auth H]
TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
SRT
Query on SRT

Download Ideal Coordinates CCD File 
PA [auth C]S,R MESO-TARTARIC ACID
C4 H6 O6
FEWJPZIEWOKRBE-XIXRPRMCSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth B]
DA [auth C]
EA [auth C]
FA [auth C]
G [auth A]
AA [auth B],
DA [auth C],
EA [auth C],
FA [auth C],
G [auth A],
GA [auth C],
H [auth A],
HA [auth C],
I [auth A],
IA [auth C],
J [auth A],
JA [auth C],
K [auth A],
KA [auth C],
L [auth A],
LA [auth C],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
Q [auth A],
QA [auth D],
RA [auth D],
U [auth B],
V [auth B],
W [auth B],
X [auth B],
XA [auth I],
Y [auth B],
Z [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MG (Subject of Investigation/LOI)
Query on MG

Download Ideal Coordinates CCD File 
MA [auth C]
R [auth A]
S [auth A]
SA [auth D]
VA [auth H]
MA [auth C],
R [auth A],
S [auth A],
SA [auth D],
VA [auth H],
YA [auth I]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free:  0.201 (Depositor), 0.209 (DCC) 
  • R-Value Work:  0.171 (Depositor), 0.182 (DCC) 
  • R-Value Observed: 0.172 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.32α = 90
b = 152.83β = 90
c = 149.15γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Swiss Cancer LeagueSwitzerlandKFS-4147-02-2017

Revision History  (Full details and data files)

  • Version 1.0: 2025-06-25
    Type: Initial release