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Dynamics of the secreted frizzled related protein Sizzled and potential implications for binding to bone morphogenetic protein-1 (BMP-1)

DOI: 10.1038/s41598-022-18795-4 DOI Help

Authors: Urvashi Sharma (UMR 5086 CNRS-University of Lyon) , Sandrine Vadon-Le Goff (UMR 5086 CNRS-University of Lyon) , Karl Harlos (The Wellcome Trust Centre for Human Genetics, University of Oxford) , Yuguang Zhao (The Wellcome Centre for Human Genetics, University of Oxford) , Natacha Mariano (UMR 5305 CNRS-University of Lyon) , Cecile Bijakowski (UMR 5305 CNRS-University of Lyon) , Jean-Marie Bourhis (UMR 5305 CNRS-University of Lyon) , Catherine Moali (UMR 5305 CNRS-University of Lyon) , David J. S. Hulmes (UMR 5305 CNRS-University of Lyon) , Nushin Aghajari (UMR 5305 CNRS-University of Lyon)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 12

State: Published (Approved)
Published: September 2022
Diamond Proposal Number(s): 8423

Open Access Open Access

Abstract: Sizzled (Szl) is both a secreted frizzled related protein (sFRP) and a naturally occurring inhibitor of the zinc metalloproteinase bone morphogenetic protein-1 (BMP-1), a key regulator of extracellular matrix assembly and growth factor activation. Here we present a new crystal structure for Szl which differs from that previously reported by a large scale (90°) hinge rotation between its cysteine-rich and netrin-like domains. We also present results of a molecular docking analysis showing interactions likely to be involved in the inhibition of BMP-1 activity by Szl. When compared with known structures of BMP-1 in complex with small molecule inhibitors, this reveals features that may be helpful in the design of new inhibitors to prevent the excessive accumulation of extracellular matrix that is the hallmark of fibrotic diseases.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS , I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Other Facilities: MX, FIP at ESRF; PX3 at Swiss Light Source; Proxima 1 at Soleil

Added On: 07/09/2022 08:34

Documents:
s41598-022-18795-4.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Scattering Macromolecular Crystallography (MX) Small Angle X-ray Scattering (SAXS)