6GJ7

CRYSTAL STRUCTURE OF KRAS G12D (GPPCP) IN COMPLEX WITH 22

Summary for 6GJ7

• Entry DOI: 10.2210/pdb6gj7/pdb
• Descriptor: GTPase KRas, MAGNESIUM ION, PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER, ... (5 entities in total)
• Functional Keywords: kras 4b, k-ras 2, ki-ras, c-k-ras, c-ki-ras, gtpase kras, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 20444.96

Authors

Kessler, D.,Mcconnell, D.M.,Mantoulidis, A. (deposition date: 2018-05-16, release date: 2019-07-31, Last modification date: 2024-01-17)

Primary citation

Kessler, D.,Gmachl, M.,Mantoulidis, A.,Martin, L.J.,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, S.W.,McConnell, D.B.
Drugging an undruggable pocket on KRAS.
Proc.Natl.Acad.Sci.USA, 116:15823-15829, 2019

PubMed Abstract: 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 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.

PubMed: 31332011
DOI: 10.1073/pnas.1904529116

Experimental method

X-RAY DIFFRACTION (1.67 Å)