6UNP

Crystal structure of the kinase domain of BMPR2-D485G

Summary for 6UNP

• Entry DOI: 10.2210/pdb6unp/pdb
• Descriptor: Bone morphogenetic protein receptor type-2, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 85829.27

Authors

Agnew, C.,Jura, N. (deposition date: 2019-10-13, release date: 2021-07-07, Last modification date: 2024-11-06)

Primary citation

Agnew, C.,Ayaz, P.,Kashima, R.,Loving, H.S.,Ghatpande, P.,Kung, J.E.,Underbakke, E.S.,Shan, Y.,Shaw, D.E.,Hata, A.,Jura, N.
Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization.
Nat Commun, 12:4950-4950, 2021

PubMed Abstract: Upon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

PubMed: 34400635
DOI: 10.1038/s41467-021-25248-5

Experimental method

X-RAY DIFFRACTION (2.3 Å)