8VJV

Structure of Human Neurolysin in complex with dynorphin A8(1-8) peptide

Summary for 8VJV

• Entry DOI: 10.2210/pdb8vjv/pdb
• Descriptor: Neurolysin, mitochondrial, Dynorphin A(1-8), ZINC ION, ... (6 entities in total)
• Functional Keywords: metallopeptidase, bioactive peptides, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 77882.77

Authors

Shi, K.,Aihara, H. (deposition date: 2024-01-08, release date: 2024-08-21)

Primary citation

Shi, K.,Bagchi, S.,Bickel, J.,Esfahani, S.H.,Yin, L.,Cheng, T.,Karamyan, V.T.,Aihara, H.
Structural basis of divergent substrate recognition and inhibition of human neurolysin.
Sci Rep, 14:18420-18420, 2024

PubMed Abstract: A zinc metallopeptidase neurolysin (Nln) processes diverse bioactive peptides to regulate signaling in the mammalian nervous system. To understand how Nln interacts with various peptides with dissimilar sequences, we determined crystal structures of Nln in complex with diverse peptides including dynorphins, angiotensin, neurotensin, and bradykinin. The structures show that Nln binds these peptides in a large dumbbell-shaped interior cavity constricted at the active site, making minimal structural changes to accommodate different peptide sequences. The structures also show that Nln readily binds similar peptides with distinct registers, which can determine whether the peptide serves as a substrate or a competitive inhibitor. We analyzed the activities and binding of Nln toward various forms of dynorphin A peptides, which highlights the promiscuous nature of peptide binding and shows how dynorphin A (1-13) potently inhibits the Nln activity while dynorphin A (1-8) is efficiently cleaved. Our work provides insights into the broad substrate specificity of Nln and may aid in the future design of small molecule modulators for Nln.

PubMed: 39117724
DOI: 10.1038/s41598-024-67639-w

Experimental method

X-RAY DIFFRACTION (2.12 Å)