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Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry Krishna Sharma , Alexander V. Strizhak , Elaine Fowler , Xuelu Wang , Wenshu Xu , Claus Hatt Jensen , Yuteng Wu , Hannah F. Sore , Yu Heng Lau , Marko Hyvonen , Laura S. Itzhaki , David R. Spring Organic & Biomolecular Chemistry 126 DOI: 10.1039/C9OB01745C Diamond Proposal Number(s): [14043] Show Abstract ▼ Abstract: The Sondheimer dialkyne is extensively used in double strain-promoted azide–alkyne cycloadditions. This reagent suffers with poor water-solubility and rapidly decomposes in aqueous solutions. This intrinsically limits its application in biological systems, and no effective solutions are currently available. Herein, we report the development of novel highly water-soluble, stable, and azide-reactive strained dialkyne reagents. To demonstrate their extensive utility, we applied our novel dialkynes to a double strain-promoted macrocyclisation strategy to generate functionalised p53-based stapled peptides for inhibiting the oncogenic p53-MDM2 interaction. These functionalised stapled peptides bind MDM2 with low nanomolar affinity and show p53 activation in a cellular environment. Overall, our highly soluble, stable and azide-reactive dialkynes offer significant advantages over the currently used Sondheimer dialkyne, and could be utilised for numerous biological applications.	Aug 2019
I03-Macromolecular Crystallography	Structure of the human myostatin precursor and determinants of growth factor latency Thomas R. Cotton , Gerhard Fischer , Xuelu Wang , Jason C. Mccoy , Magdalena Czepnik , Thomas B Thompson , Marko Hyvonen The Embo Journal DOI: 10.15252/embj.201797883 Diamond Proposal Number(s): [14043] Show Abstract ▼ Abstract: Myostatin, a key regulator of muscle mass in vertebrates, is biosynthesised as a latent precursor in muscle and is activated by sequential proteolysis of the pro-domain. To investigate the molecular mechanism by which pro-myostatin remains latent, we have determined the structure of unprocessed pro-myostatin and analysed the properties of the protein in its different forms. Crystal structures and SAXS analyses show that pro-myostatin adopts an open, V-shaped structure with a domain-swapped arrangement. The pro-mature complex, after cleavage of the furin site, has significantly reduced activity compared with the mature growth factor and persists as a stable complex that is resistant to the natural antagonist follistatin. The latency appears to be conferred by a number of distinct features that collectively stabilise the interaction of the pro-domains with the mature growth factor, enabling a regulated stepwise activation process, distinct from the prototypical pro-TGF-β1. These results provide a basis for understanding the effect of missense mutations in pro-myostatin and pave the way for the design of novel myostatin inhibitors.	Jan 2018
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Structure and activation of pro-activin A Xuelu Wang , Gerhard Fischer , Marko Hyvonen Nature Communications 7 DOI: 10.1038/ncomms12052 Diamond Proposal Number(s): [7141, 8094, 9007, 9537] Open Access Show Abstract ▼ Abstract: Activins are growth factors with multiple roles in the development and homeostasis. Like all TGF-β family of growth factors, activins are synthesized as large precursors from which mature dimeric growth factors are released proteolytically. Here we have studied the activation of activin A and determined crystal structures of the unprocessed precursor and of the cleaved pro-mature complex. Replacing the natural furin cleavage site with a HRV 3C protease site, we show how the protein gains its bioactivity after proteolysis and is as active as the isolated mature domain. The complex remains associated in conditions used for biochemical analysis with a dissociation constant of 5 nM, but the pro-domain can be actively displaced from the complex by follistatin. Our high-resolution structures of pro-activin A share features seen in the pro-TGF-β1 and pro-BMP-9 structures, but reveal a new oligomeric arrangement, with a domain-swapped, cross-armed conformation for the protomers in the dimeric protein.	Jul 2016
B21-High Throughput SAXS I04-Macromolecular Crystallography	Structure of Gremlin-1 and analysis of its interaction with BMP-2 Migle Kisonaite , Xuelu Wang , Marko Hyvonen Biochemical Journal DOI: 10.1042/BCJ20160254 Diamond Proposal Number(s): [9537] Show Abstract ▼ Abstract: Bone morphogenetic protein 2 (BMP-2) is a member of the transforming growth factor-β (TGF-β) signaling family and has a very broad biological role in development. Its signaling is regulated by many effectors: transmembrane proteins, membrane attached proteins and soluble secreted antagonists such as Gremlin-1. Very little is known about the molecular mechanism by which Gremlin-1 and other DAN family proteins inhibit BMP signaling. We analyzed the interaction of Gremlin-1 with BMP-2 using a range of biophysical techniques, and used mutagenesis to map the binding site on BMP-2. We have also determined the crystal structure of Gremlin-1, revealing a similar conserved dimeric structure as has been seen in other DAN family inhibitors. Measurements using biolayer interferometry indicate that Gremlin-1 and BMP-2 can form larger complexes, beyond the expected 1:1 stoichiometry of dimers, forming oligomers that assemble in alternating fashion. These results suggest that inhibition of BMP-2 by Gremlin-1 occurs by a mechanism that is distinct from other known inhibitors such as Noggin and Chordin and we propose a novel model of BMP-2/Gremlin-1 interaction yet not seen among any BMP antagonists, and cannot rule out that several different oligomeric states could be found, depending on the concentration of the two proteins.	Apr 2016

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