6EEY

Crystal structure of human Scribble PDZ4 R1110G Mutant

Summary for 6EEY

• Entry DOI: 10.2210/pdb6eey/pdb
• Descriptor: Protein scribble homolog (2 entities in total)
• Functional Keywords: pdz domain, cell polarity, structural protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 9979.45

Authors

Janezic, E.M.,Hsu, P.,Hague, C. (deposition date: 2018-08-15, release date: 2019-10-02, Last modification date: 2023-10-11)

Primary citation

Janezic, E.M.,Harris, D.A.,Dinh, D.,Lee, K.S.,Stewart, A.,Hinds, T.R.,Hsu, P.L.,Zheng, N.,Hague, C.
Scribble co-operatively binds multiple alpha1D-adrenergic receptor C-terminal PDZ ligands.
Sci Rep, 9:14073-14073, 2019

PubMed Abstract: Many G protein-coupled receptors (GPCRs) are organized as dynamic macromolecular complexes in human cells. Unraveling the structural determinants of unique GPCR complexes may identify unique protein:protein interfaces to be exploited for drug development. We previously reported α-adrenergic receptors (α-ARs) - key regulators of cardiovascular and central nervous system function - form homodimeric, modular PDZ protein complexes with cell-type specificity. Towards mapping α-AR complex architecture, biolayer interferometry (BLI) revealed the α-AR C-terminal PDZ ligand selectively binds the PDZ protein scribble (SCRIB) with >8x higher affinity than known interactors syntrophin, CASK and DLG1. Complementary in situ and in vitro assays revealed SCRIB PDZ domains 1 and 4 to be high affinity α-AR PDZ ligand interaction sites. SNAP-GST pull-down assays demonstrate SCRIB binds multiple α-AR PDZ ligands via a co-operative mechanism. Structure-function analyses pinpoint R1110 as a unique, critical residue dictating SCRIB:α-AR binding specificity. The crystal structure of SCRIB PDZ4 R1110G predicts spatial shifts in the SCRIB PDZ4 carboxylate binding loop dictate α-AR binding specificity. Thus, the findings herein identify SCRIB PDZ domains 1 and 4 as high affinity α-AR interaction sites, and potential drug targets to treat diseases associated with aberrant α-AR signaling.

PubMed: 31575922
DOI: 10.1038/s41598-019-50671-6

Experimental method

X-RAY DIFFRACTION (1.145 Å)