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Structural consequences of BMPR2 kinase domain mutations causing pulmonary arterial hypertension

DOI: 10.1038/s41598-019-54830-7 DOI Help

Authors: Apirat Chaikuad (Structural Genomics Consortium, University of Oxford; Structural Genomics Consortium Goethe-University Frankfurt) , Chancievan Thangaratnarajah (Structural Genomics Consortium, University of Oxford; University of Groningen) , Frank Von Delft (tructural Genomics Consortium, University of Oxford; Diamond Light Source; University of Johannesburg) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 9

State: Published (Approved)
Published: December 2019

Open Access Open Access

Abstract: 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.

Journal Keywords: Biochemistry; Genetics; Molecular biology; Molecular medicine; Structural biology

Diamond Keywords: Cardiovascular Disease; Pulmonary Arterial Hypertension

Subject Areas: Biology and Bio-materials, Chemistry

Facility: Swiss Light Source (SLS)

Added On: 11/12/2019 15:32


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Non-Communicable Diseases Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Life Sciences & Biotech

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