6SF3

Bone morphogenetic protein 10 (BMP10) in complex with extracellular domain of activin receptor-like kinase 1 (ALK1) at 2.3 Angstrom

Summary for 6SF3

• Entry DOI: 10.2210/pdb6sf3/pdb
• Related: 6SF1
• Descriptor: Serine/threonine-protein kinase receptor R3, Bone morphogenetic protein 10 (3 entities in total)
• Functional Keywords: bmp10, alk1, complex, signalling, tgfbeta, bmp, cytokine
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 22965.31

Authors

Guo, J.,Yu, M.,Li, W. (deposition date: 2019-07-31, release date: 2020-04-08, Last modification date: 2024-01-24)

Primary citation

Salmon, R.M.,Guo, J.,Wood, J.H.,Tong, Z.,Beech, J.S.,Lawera, A.,Yu, M.,Grainger, D.J.,Reckless, J.,Morrell, N.W.,Li, W.
Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms.
Nat Commun, 11:1621-1621, 2020

PubMed Abstract: Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 Å and the prodomain-bound BMP9:ALK1 complex at 3.3 Å. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway.

PubMed: 32238803
DOI: 10.1038/s41467-020-15425-3

Experimental method

X-RAY DIFFRACTION (2.3000067422 Å)