Stabilization of the retromer complex: analysis of novel binding sites of bis-1,3-phenyl guanylhydrazone 2a to the VPS29/VPS35 interface

DOI: 10.1016/j.csbj.2024.02.026

Authors: Elisa Fagnani (CNR-IBF; University of Milan) , Francesco Boni (CNR-IBF; University of Milan) , Pierfausto Seneci (University of Milan) , Davide Gornati (University of Milan) , Luca Muzio (INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute) , Eloise Mastrangelo (CNR-IBF; University of Milan) , Mario Milani (CNR-IBF; University of Milan)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Computational And Structural Biotechnology Journal , VOL 1–2

State: Published (Approved)
Published: March 2024

Abstract: The stabilization of the retromer protein complex can be effective in the treatment of different neurological disorders. Following the identification of bis-1,3-phenyl guanylhydrazone 2a as an effective new compound for the treatment of amyotrophic lateral sclerosis, in this work we analyze the possible binding sites of this molecule to the VPS35/VPS29 dimer of the retromer complex. Our results show that the affinity for different sites of the protein assembly depends on compound charge and therefore slight changes in the cell microenvironment could promote different binding states. Finally, we describe a novel binding site located in a deep cleft between VPS29 and VPS35 that should be further explored to select novel molecular chaperones for the stabilization of the retromer complex.

Journal Keywords: Crystal structure; molecular dynamics simulations; protein ligand interaction; protein binding sites

Diamond Keywords: Motor Neurone Disease

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ID23-2 at ESRF

Added On: 05/03/2024 09:59

Documents:
1-s2.0-S2001037024000503-main.pdf

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)