21ZX

Crystal structure of Gephyrin E domain with PX-RICS peptide

Summary for 21ZX

• Entry DOI: 10.2210/pdb21zx/pdb
• Descriptor: Isoform 5 of Gephyrin, Rho GTPase-activating protein 32, GLYCEROL, ... (5 entities in total)
• Functional Keywords: px-rics, arhgap32, gephyrin, complex, protein binding
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 6
• Total formula weight: 196368.26

Authors

Bai, G.,Zhang, M.,Yang, W. (deposition date: 2026-01-05, release date: 2026-07-15, Last modification date: 2026-08-05)

Primary citation

Bai, G.,Huang, R.,Lian, Y.,Zhao, X.,Yang, W.,Lu, X.,Li, H.,Zhang, M.
The ARHGAP32 isoform PX-RICS is specifically targeted to inhibitory synapses by binding to gephyrin.
Proc.Natl.Acad.Sci.USA, 123:-, 2026

PubMed Abstract: Precise regulation of excitatory-inhibitory balance is critical for neural circuit function, and its disruption underlies neurodevelopmental disorders such as autism spectrum disorder (ASD) and epilepsy. PX-RICS, a major splice variant enriched at inhibitory synapses, has been linked to cognitive dysfunctions; however, the molecular basis of its synaptic targeting and function remains unknown. Here, we identify gephyrin as the primary synaptic anchor for PX-RICS and determine the 2.2 Å crystal structure of their complex. Our structural analysis reveals that the N-terminal gephyrin-binding region (GBR) engages gephyrin E-domain through conserved hydrophobic interactions, explaining the isoform-specific targeting of PX-RICS (but not RICS) to inhibitory synapses. This binding interface overlaps with the neurotransmitter receptor binding site on gephyrin, suggesting a competitive yet dynamic interaction landscape among these inhibitory synaptic proteins. mice exhibit key features of -related disorders, including impaired social novelty recognition and increased seizure susceptibility, indicating that gephyrin-mediated anchoring is critical for PX-RICS to function in inhibitory synapses.

PubMed: 42479840
DOI: 10.1073/pnas.2601488123

Experimental method

X-RAY DIFFRACTION (2.2 Å)