Publication

Structural consequences of BMPR2 kinase domain mutations causing pulmonary arterial hypertension

Chaikuad, A., Thangaratnarajah, C., von Delft, F. & Bullock, A. N., 4-Dec-2019, In : Scientific Reports. 9, 1, 18351.

Research output: Contribution to journalArticleAcademicpeer-review

Bone morphogenetic proteins (BMPs) are secreted ligands of the transforming growth factor-β (TGF-β) family that control embryonic patterning, as well as tissue development and homeostasis. Loss of function mutations in the type II BMP receptor BMPR2 are the leading cause of pulmonary arterial hypertension (PAH), a rare disease of vascular occlusion that leads to high blood pressure in the pulmonary arteries. To understand the structural consequences of these mutations, we determined the crystal structure of the human wild-type BMPR2 kinase domain at 2.35 Å resolution. The structure revealed an active conformation of the catalytic domain that formed canonical interactions with the bound ligand Mg-ADP. Disease-associated missense mutations were mapped throughout the protein structure, but clustered predominantly in the larger kinase C-lobe. Modelling revealed that the mutations will destabilize the protein structure by varying extents consistent with their previously reported functional heterogeneity. The most severe mutations introduced steric clashes in the hydrophobic protein core, whereas those found on the protein surface were less destabilizing and potentially most favorable for therapeutic rescue strategies currently under clinical investigation.

Original languageEnglish
Article number18351
JournalScientific Reports
Volume9
Issue number1
Publication statusPublished - 4-Dec-2019
Externally publishedYes

    Keywords

  • II RECEPTOR

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