6ar4

From Proteopedia

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

PDB ID 6ar4

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Structural highlights

6ar4 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.69Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PICK1_HUMAN Probable adapter protein that bind to and organize the subcellular localization of a variety of membrane proteins containing some PDZ recognition sequence. Involved in the clustering of various receptors, possibly by acting at the receptor internalization level. Plays a role in synaptic plasticity by regulating the trafficking and internalization of AMPA receptors. May be regulated upon PRKCA activation. May regulate heteromeric ASIC1/ASIC3 channel.^[1]

Publication Abstract from PubMed

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 Abeta-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.

Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction.,Lin EYS, Silvian LF, Marcotte DJ, Banos CC, Jow F, Chan TR, Arduini RM, Qian F, Baker DP, Bergeron C, Hession CA, Huganir RL, Borenstein CF, Enyedy I, Zou J, Rohde E, Wittmann M, Kumaravel G, Rhodes KJ, Scannevin RH, Dunah AW, Guckian KM Sci Rep. 2018 Sep 7;8(1):13438. doi: 10.1038/s41598-018-31680-3. PMID:30194389^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Shao X, Zhu L, Wang Y, Lu Y, Wang W, Zhu J, Shen Y, Xia J, Luo J. Threonine 82 at the PDZ domain of PICK1 is critical for AMPA receptor interaction and localization. Neurochem Int. 2010 Jul;56(8):962-70. doi: 10.1016/j.neuint.2010.04.006. Epub, 2010 Apr 18. PMID:20403402 doi:http://dx.doi.org/10.1016/j.neuint.2010.04.006
↑ Lin EYS, Silvian LF, Marcotte DJ, Banos CC, Jow F, Chan TR, Arduini RM, Qian F, Baker DP, Bergeron C, Hession CA, Huganir RL, Borenstein CF, Enyedy I, Zou J, Rohde E, Wittmann M, Kumaravel G, Rhodes KJ, Scannevin RH, Dunah AW, Guckian KM. Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction. Sci Rep. 2018 Sep 7;8(1):13438. doi: 10.1038/s41598-018-31680-3. PMID:30194389 doi:http://dx.doi.org/10.1038/s41598-018-31680-3