3ZRT

Crystal structure of human PSD-95 PDZ1-2

Summary for 3ZRT

• Entry DOI: 10.2210/pdb3zrt/pdb
• Related: 1KEF
• Descriptor: DISKS LARGE HOMOLOG 4 (1 entity in total)
• Functional Keywords: signaling protein
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 4
• Total formula weight: 85389.31

Authors

Sorensen, P.L.,Kastrup, J.S.,Gajhede, M. (deposition date: 2011-06-19, release date: 2012-03-21, Last modification date: 2023-12-20)

Primary citation

Bach, A.,Clausen, B.H.,Moller, M.,Vestergaard, B.,Chi, C.N.,Round, A.,Sorensen, P.L.,Nissen, K.B.,Kastrup, J.S.,Gajhede, M.,Jemth, P.,Kristensen, A.S.,Lundstrom, P.,Lambertsen, K.L.,Stromgaard, K.
A High-Affinity, Dimeric Inhibitor of Psd-95 Bivalently Interacts with Pdz1-2 and Protects Against Ischemic Brain Damage.
Proc.Natl.Acad.Sci.USA, 109:3317-, 2012

PubMed Abstract: Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.

PubMed: 22343531
DOI: 10.1073/PNAS.1113761109

Experimental method

X-RAY DIFFRACTION (3.398 Å)