6AR4

Crystal structure of PICK1 in complex with the small molecule inhibitor 1o

Summary for 6AR4

• Entry DOI: 10.2210/pdb6ar4/pdb
• Descriptor: PRKCA-binding protein, N-[4-(4-bromophenyl)-1-{[2-(trifluoromethyl)phenyl]methyl}piperidine-4-carbonyl]-3-cyclopropyl-L-alanine (3 entities in total)
• Functional Keywords: pdz domain pdz inhibitor, actin binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28187.63

Authors

Marcotte, D. (deposition date: 2017-08-21, release date: 2018-08-22, Last modification date: 2024-10-23)

Primary citation

Lin, E.Y.S.,Silvian, L.F.,Marcotte, D.J.,Banos, C.C.,Jow, F.,Chan, T.R.,Arduini, R.M.,Qian, F.,Baker, D.P.,Bergeron, C.,Hession, C.A.,Huganir, R.L.,Borenstein, C.F.,Enyedy, I.,Zou, J.,Rohde, E.,Wittmann, M.,Kumaravel, G.,Rhodes, K.J.,Scannevin, R.H.,Dunah, A.W.,Guckian, K.M.
Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction.
Sci Rep, 8:13438-13438, 2018

PubMed Abstract: Protein interacting with C kinase (PICK1) is a scaffolding protein that is present in dendritic spines and interacts with a wide array of proteins through its PDZ domain. The best understood function of PICK1 is regulation of trafficking of AMPA receptors at neuronal synapses via its specific interaction with the AMPA GluA2 subunit. Disrupting the PICK1-GluA2 interaction has been shown to alter synaptic plasticity, a molecular mechanism of learning and memory. Lack of potent, selective inhibitors of the PICK1 PDZ domain has hindered efforts at exploring the PICK1-GluA2 interaction as a therapeutic target for neurological diseases. Here, we report the discovery of PICK1 small molecule inhibitors using a structure-based drug design strategy. The inhibitors stabilized surface GluA2, reduced Aβ-induced rise in intracellular calcium concentrations in cultured neurons, and blocked long term depression in brain slices. These findings demonstrate that it is possible to identify potent, selective PICK1-GluA2 inhibitors which may prove useful for treatment of neurodegenerative disorders.

PubMed: 30194389
DOI: 10.1038/s41598-018-31680-3

Experimental method

X-RAY DIFFRACTION (1.69 Å)