8BI8

Structure of a cyclic beta-hairpin peptide derived from neuronal nitric oxide synthase

Summary for 8BI8

• Entry DOI: 10.2210/pdb8bi8/pdb
• Descriptor: Nitric oxide synthase, brain (2 entities in total)
• Functional Keywords: cyclic beta-hairpin, neuronal nitric oxidase synthase, inhibitor of the nos/psd-95 interaction, peptide drugs, stroke treatment, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 4977.45

Authors

Balboa, J.R.,Ostergaard, S.,Stromgaard, K.,Knapp, S.,Joerger, A.C.,Structural Genomics Consortium (SGC) (deposition date: 2022-11-01, release date: 2022-12-21, Last modification date: 2024-11-13)

Primary citation

Balboa, J.R.,Essig, D.J.,Ma, S.,Karer, N.,Clemmensen, L.S.,Pedersen, S.W.,Joerger, A.C.,Knapp, S.,Ostergaard, S.,Stromgaard, K.
Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction.
J.Med.Chem., 66:976-990, 2023

PubMed Abstract: The complex between the -methyl-d-aspartate receptor (NMDAR), neuronal nitric oxide synthase (nNOS), and the postsynaptic density protein-95 (PSD-95) is an attractive therapeutic target for the treatment of acute ischemic stroke. The complex is formed via the PDZ protein domains of PSD-95, and efforts to disrupt the complex have generally been based on C-terminal peptides derived from the NMDAR. However, nNOS binds PSD-95 through a β-hairpin motif, providing an alternative starting point for developing PSD-95 inhibitors. Here, we designed a cyclic nNOS β-hairpin mimetic peptide and generated cyclic nNOS β-hairpin peptide arrays with natural and unnatural amino acids (AAs), which provided molecular insights into this interaction. We then optimized cyclic peptides and identified a potent inhibitor of the nNOS/PSD-95 interaction, with the highest affinity reported thus far for a peptide macrocycle inhibitor of PDZ domains, which serves as a template for the development of treatment for acute ischemic stroke.

PubMed: 36580549
DOI: 10.1021/acs.jmedchem.2c01803

Experimental method

X-RAY DIFFRACTION (1.59 Å)