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Instruments / Technical Area	Publication Details	Published
	Structural consequences of BMPR2 kinase domain mutations causing pulmonary arterial hypertension Apirat Chaikuad , Chancievan Thangaratnarajah , Frank Von Delft , Alex N. Bullock Scientific Reports 9 DOI: 10.1038/s41598-019-54830-7 Open Access Show Abstract ▼ 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.	Dec 2019
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers Chancievan Thangaratnarajah , Jonathan Ruprecht , Edmund Kunji Nature Communications 5 DOI: 10.1038/ncomms6491 PMID: 25410934 Diamond Proposal Number(s): [6641, 8547] Open Access Show Abstract ▼ Abstract: The transport activity of human mitochondrial aspartate/glutamate carriers is central to the malate–aspartate shuttle, urea cycle, gluconeogenesis and myelin synthesis. They have a unique three-domain structure, comprising a calcium-regulated N-terminal domain with eight EF-hands, a mitochondrial carrier domain, and a C-terminal domain. Here we present the calcium-bound and calcium-free structures of the N- and C-terminal domains, elucidating the mechanism of calcium regulation. Unexpectedly, EF-hands 4–8 are involved in dimerization of the carrier and form a static unit, whereas EF-hands 1–3 form a calcium-responsive mobile unit. On calcium binding, an amphipathic helix of the C-terminal domain binds to the N-terminal domain, opening a vestibule. In the absence of calcium, the mobile unit closes the vestibule. Opening and closing of the vestibule might regulate access of substrates to the carrier domain, which is involved in their transport. These structures provide a framework for understanding cases of the mitochondrial disease citrin deficiency.	Nov 2014
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Structural basis for Cul3 assembly with the BTB-Kelch family of E3 ubiquitin ligases Peter Canning , Christopher D. O. Cooper , Tobias Krojer , James W. Murray , Ashley C. W. Pike , Apirat Chaikuad , Tracy Keates , Chancievan Thangaratnarajah , Viktorija Hojzan , Brian D. Marsden , Opher Gileadi , Stefan Knapp , Frank Von Delft , Alex N. Bullock Journal Of Biological Chemistry DOI: 10.1074/jbc.M112.437996 PMID: 23349464 Open Access Show Abstract ▼ Abstract: Cullin-RING ligases are multisubunit E3 ubiquitin ligases that recruit substrate-specific adaptors to catalyze protein ubiquitylation. Cul3-based Cullin-RING ligases are uniquely associated with BTB adaptors that incorporate homodimerization, Cul3 assembly, and substrate recognition into a single multidomain protein, of which the best known are BTB-BACK-Kelch domain proteins, including KEAP1. Cul3 assembly requires a BTB protein “3-box” motif, analogous to the F-box and SOCS box motifs of other Cullin-based E3s. To define the molecular basis for this assembly and the overall architecture of the E3, we determined the crystal structures of the BTB-BACK domains of KLHL11 both alone and in complex with Cul3, along with the Kelch domain structures of KLHL2 (Mayven), KLHL7, KLHL12, and KBTBD5. We show that Cul3 interaction is dependent on a unique N-terminal extension sequence that packs against the 3-box in a hydrophobic groove centrally located between the BTB and BACK domains. Deletion of this N-terminal region results in a 30-fold loss in affinity. The presented data offer a model for the quaternary assembly of this E3 class that supports the bivalent capture of Nrf2 and reveals potential new sites for E3 inhibitor design.	Jan 2013

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