3g2f
From Proteopedia
Crystal structure of the kinase domain of bone morphogenetic protein receptor type II (BMPR2) at 2.35 A resolution
Structural highlights
Disease[BMPR2_HUMAN] Defects in BMPR2 are the cause of primary pulmonary hypertension (PPH1) [MIM:178600]. PPH1 is a rare autosomal dominant disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.[1] [2] [3] [4] [5] [6] Defects in BMPR2 are a cause of pulmonary venoocclusive disease (PVOD) [MIM:265450]. PVOD is a rare form of pulmonary hypertension in which the vascular changes originate in the small pulmonary veins and venules. The pathogenesis is unknown and any link with PPH1 has been speculative. The finding of PVOD associated with a BMPR2 mutation reveals a possible pathogenetic connection with PPH1.[7] [8] Function[BMPR2_HUMAN] On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP-7, BMP-2 and, less efficiently, BMP-4. Binding is weak but enhanced by the presence of type I receptors for BMPs. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBone morphogenetic proteins (BMPs) are secreted ligands of the transforming growth factor-beta (TGF-beta) 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 A 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. Structural consequences of BMPR2 kinase domain mutations causing pulmonary arterial hypertension.,Chaikuad A, Thangaratnarajah C, von Delft F, Bullock AN Sci Rep. 2019 Dec 4;9(1):18351. doi: 10.1038/s41598-019-54830-7. PMID:31797984[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Receptor protein serine/threonine kinase | Arrowsmith, C H | Bountra, C | Bullock, A | Chaikuad, A | Chalk, R | Delft, F von | Edwards, A M | Fedorov, O | Filippakopoulos, P | Keates, T | Knapp, S | Petrie, K | Phillips, C | Pike, A C.W | Roos, A K | Structural genomic | Salah, E | Thangaratnarajah, C | Weigelt, J | Atp-binding | Disease mutation | Glycoprotein | Kinase | Magnesium | Manganese | Membrane | Metal-binding | Nucleotide-binding | Phosphoprotein | Receptor | Serine/threonine-protein kinase | Sgc | Transferase | Transmembrane
