6NBS

WT ERK2 with compound 2507-8

Summary for 6NBS

• Entry DOI: 10.2210/pdb6nbs/pdb
• Descriptor: Mitogen-activated protein kinase 1, SULFATE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: inhibitor, mapk, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 1
• Total formula weight: 43270.85

Authors

Sammons, R.M.,Perry, N.A.,Cho, E.J.,Kaoud, T.S.,Zamora-Olivares, D.P.,Piserchio, A.,Houghten, R.A.,Giulianotti, M.,Li, Y.,Debevec, G.,Gurevich, V.V.,Ghose, R.,Iverson, T.M.,Dalby, K.N. (deposition date: 2018-12-10, release date: 2019-07-31, Last modification date: 2023-10-11)

Primary citation

Sammons, R.M.,Perry, N.A.,Li, Y.,Cho, E.J.,Piserchio, A.,Zamora-Olivares, D.P.,Ghose, R.,Kaoud, T.S.,Debevec, G.,Bartholomeusz, C.,Gurevich, V.V.,Iverson, T.M.,Giulianotti, M.,Houghten, R.A.,Dalby, K.N.
A Novel Class of Common Docking Domain Inhibitors That Prevent ERK2 Activation and Substrate Phosphorylation.
Acs Chem.Biol., 14:1183-1194, 2019

PubMed Abstract: Extracellular signal-regulated kinases (ERK1/2) are mitogen-activated protein kinases (MAPKs) that play a pro-tumorigenic role in numerous cancers. ERK1/2 possess two protein-docking sites that are distinct from the active site: the D-recruitment site (DRS) and the F-recruitment site. These docking sites facilitate substrate recognition, intracellular localization, signaling specificity, and protein complex assembly. Targeting these sites on ERK in a therapeutic context may overcome many problems associated with traditional ATP-competitive inhibitors. Here, we identified a new class of inhibitors that target the ERK DRS by screening a synthetic combinatorial library of more than 30 million compounds. The screen detects the competitive displacement of a fluorescent peptide from the DRS of ERK2. The top molecular scaffold from the screen was optimized for structure-activity relationship by positional scanning of different functional groups. This resulted in 10 compounds with similar binding affinities and a shared core structure consisting of a tertiary amine hub with three functionalized cyclic guanidino branches. Compound 2507-1 inhibited ERK2 from phosphorylating a DRS-targeting substrate and prevented the phosphorylation of ERK2 by a constitutively active MEK1 (MAPK/ERK kinase 1) mutant. Interaction between an analogue, 2507-8, and the ERK2 DRS was confirmed by nuclear magnetic resonance and X-ray crystallography. 2507-8 forms critical interactions at the common docking domain residue Asp319 via an arginine-like moiety that is shared by all 10 hits, suggesting a common binding mode. The structural and biochemical insights reported here provide the basis for developing new ERK inhibitors that are not ATP-competitive but instead function by disrupting critical protein-protein interactions.

PubMed: 31058487
DOI: 10.1021/acschembio.9b00093

Experimental method

X-RAY DIFFRACTION (1.9 Å)