6ARK

Crystal Structure of compound 10 covalently bound to K-Ras G12C

Summary for 6ARK

• Entry DOI: 10.2210/pdb6ark/pdb
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: dockovalent, covalent docking, k-ras g12c, covalent inhibitors, covalent fragments, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 20395.74

Authors

Nnadi, C.I.,Jenkins, M.L.,Gentile, D.R.,Bateman, L.A.,Zaidman, D.,Balius, T.E.,Nomura, D.K.,Burke, J.E.,Shokat, K.M.,London, N. (deposition date: 2017-08-22, release date: 2018-01-31, Last modification date: 2024-10-16)

Primary citation

Nnadi, C.I.,Jenkins, M.L.,Gentile, D.R.,Bateman, L.A.,Zaidman, D.,Balius, T.E.,Nomura, D.K.,Burke, J.E.,Shokat, K.M.,London, N.
Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange.
J Chem Inf Model, 58:464-471, 2018

PubMed Abstract: The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to a lack of methodological development. Here, we compared covalent docking to empirical electrophile screening against the highly dynamic target K-Ras. While the overall hit rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent binder that modifies the inactive, GDP-bound state of K-Ras. Hydrogen-deuterium exchange mass spectrometry was used to probe the protein dynamics of compound binding to the switch-II pocket and subsequent destabilization of the nucleotide-binding region. SOS-mediated nucleotide exchange assays showed that, contrary to prior switch-II pocket inhibitors, these new compounds appear to accelerate nucleotide exchange. This study highlights the efficiency of covalent docking as a tool for the discovery of chemically novel hits against challenging targets.

PubMed: 29320178
DOI: 10.1021/acs.jcim.7b00399

Experimental method

X-RAY DIFFRACTION (1.75 Å)