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Abstract: The second domain of gelsolin (G2) hosts mutations responsible for a hereditary form of amyloidosis. The active form of gelsolin is Ca2+-bound; it is also a dynamic protein, hence structural biologists often rely on the study of the isolated G2. However, the wild type G2 structure that have been used so far in comparative studies is bound to a crystallographic Cd2+, in lieu of the physiological calcium. Here, we report the wild type structure of G2 in complex with Ca2+ highlighting subtle ion-dependent differences. Previous findings on different G2 mutations are also briefly revised in light of these results.

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Abstract: Enzyme transition-state mimics can act as powerful inhibitors and allow structural studies that report on the conformation of the transition-state. Here, mannoimidazole, a mimic of the transition state of mannosidase catalyzed hydrolysis of mannosides, is shown to bind in a B2,5 conformation on the Clostridium perfringens GH125 α-1,6-mannosidase, providing additional evidence of a OS2–B2,5–1S5 conformational itinerary for enzymes of this family.

Open Access

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Abstract: Molecular crystals can be bent elastically by expansion or plastically by delamination into slabs that glide along slip planes. Here we report that upon bending, terephthalic acid crystals can undergo a mechanically induced phase transition without delamination and their overall crystal integrity is retained. Such plastically bent crystals act as bimorphs and their phase uniformity can be recovered thermally by taking the crystal over the phase transition temperature. This recovers the original straight shape and the crystal can be bent by a reverse thermal treatment, resulting in shape memory effects akin of those observed with some metal alloys and polymers. We anticipate that similar memory and restorative effects are common for other molecular crystals having metastable polymorphs. The results demonstrate the advantage of using intermolecular interactions to accomplish mechanically adaptive properties with organic solids that bridge the gap between mesophasic and inorganic materials in the materials property space.

Open Access

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Abstract: Coccolithophores are marine phytoplankton that are among the most prolific calcifiers widespread in Earth’s oceans, playing a crucial role in the carbon cycle and in the transport of organic matter to the deep sea. These organisms produce highly complex mineralized scales that are composed of hierarchical assemblies of nano-crystals of calcium carbonate in the form of calcite. Coccolith formation in vivo occurs within compartmentalized mineralisation vesicles derived from the Golgi body, which contain coccolith-associated polysaccharides (‘CAPs’) providing polymorph selection and mediating crystal growth kinetics, and oval organic mineralisation templates, also known as base plates, which promote heterogenous nucleation and further mechanical interlocking of calcite single crystals. Although the function of coccolith base plates in controlling crystal nucleation have been widely studied, their 3D spatial organization and the chemical functional groups present on the crystal nucleation sites, which are two crucial features impacting biomineralization, remain unsolved. Utilising cryo-electron tomography we show that base plates derived from an exemplary coccolithophore Pleurochrysis carterae (Pcar) in their native hydrated state have a complex 3-layered structure. We further demonstrate, for the first time, the edge and rim of the base plate – where the crystals nucleate - are rich in primary amine functionalities that provide binding targets for negatively charged complexes composed of synthetic macromolecules and Ca2+ ions. Our results indicate that electrostatic interactions between the negatively charged biogenic CAPs and the positively charged rim of the base plate are sufficient to mediate the transport of Ca2+ cations to the mineralization sites.

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Abstract: Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Towards this end we report here the first crystal structures of the recent clinically-observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase which could have implications for small molecule in-hibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.