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Instruments / Technical Area	Publication Details	Published
NONE-No attached Diamond beamline	A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint Kevin P. Guay , Roberta Ibba , John L. Kiappes , Snežana Vasiljević , Francesco Bonì , Maria De Benedictis , Ilaria Zeni , James D. Le Cornu , Mario Hensen , Anu V. Chandran , Anastassia L. Kantsadi , Alessandro T. Caputo , Juan I. Blanco Capurro , Yusupha Bayo , Johan C. Hill , Kieran Hudson , Andrea Lia , Juliane Brun , Stephen G. Withers , Marcelo Martí , Emiliano Biasini , Angelo Santino , Matteo De Rosa , Mario Milani , Carlos P. Modenutti , Daniel N. Hebert , Nicole Zitzmann , Pietro Roversi Iscience DOI: 10.1016/j.isci.2023.107919 Diamond Proposal Number(s): [19758] Open Access Show Abstract ▼ Abstract: Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding Quality Control (ERQC) checkpoint enzyme, UDP-Glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a CtUGGTGT24 ‘WY’ conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 μM binding affinity for CtUGGTGT24 in vitro as measured by ligand-enhanced fluorescence. In cellula, 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to CtUGGTGT24 appears to be mutually exclusive to M5-9 glycan binding in an in vitro competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors.	Sep 2023
I04-Macromolecular Crystallography	A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation Michela Bollati , Luisa Diomede , Toni Giorgino , Carmina Natale , Elisa Fagnani , Irene Boniardi , Alberto Barbiroli , Rebecca Alemani , Marten Beeg , Marco Gobbi , Ana Fakin , Eloise Mastrangelo , Mario Milani , Gianluca Presciuttini , Edi Gabellieri , Patrizia Cioni , Matteo De Rosa Computational And Structural Biotechnology Journal 281 DOI: 10.1016/j.csbj.2021.11.025 Diamond Proposal Number(s): [20221] Open Access Show Abstract ▼ Abstract: Gelsolin comprises six homologous domains, named G1 to G6. Single point substitutions in this protein are responsible for AGel amyloidosis, a hereditary disease causing progressive corneal lattice dystrophy, cutis laxa, and polyneuropathy. Although several different amyloidogenic variants of gelsolin have been identified, only the most common mutants present in the G2 domain have been thoroughly characterized, leading to clarification of the functional mechanism. The molecular events underlying the pathological aggregation of 3 recently identified mutations, namely A551P, E553K and M517R, all localized at the interface between G4 and G5, are here explored for the first time. . Structural studies point to destabilization of the interface between G4 and G5 due to three structural determinants: β-strand breaking, steric hindrance and/or charge repulsion, all implying impairment of interdomain contacts. Such rearrangements decrease the temperature and pressure stability of gelsolin but do not alter its susceptibility to furin cleavage, the first event in the canonical aggregation pathway. These variants also have a greater tendency to aggregate in the unproteolysed forms and exhibit higher proteotoxicity in a C. elegans-based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway.	Nov 2021
B21-High Throughput SAXS	Missense mutations affecting Ca2+-coordination in GCAP1 lead to cone-rod dystrophies by altering protein structural and functional properties Giuditta Dal Cortivo , Valerio Marino , Francesco Boni , Mario Milani , Daniele Dell'Orco Biochimica Et Biophysica Acta (bba) - Molecular Cell Research DOI: 10.1016/j.bbamcr.2020.118794 Diamond Proposal Number(s): [20221] Show Abstract ▼ Abstract: Guanylate cyclase activating protein 1 (GCAP1) is a neuronal calcium sensor (NCS) involved in the early biochemical steps underlying the phototransduction cascade. By switching from a Ca2+-bound form in the dark to a Mg2+-bound state following light activation of the cascade, GCAP1 triggers the activation of the retinal guanylate cyclase (GC), thus replenishing the levels of 3′,5′-cyclic monophosphate (cGMP) necessary to re-open CNG channels. Here, we investigated the structural and functional effects of three missense mutations in GCAP1 associated with cone-rod dystrophy, which severely perturb the homeostasis of cGMP and Ca2+. Substitutions affect residues directly involved in Ca2+ coordination in either EF3 (D100G) or EF4 (E155A and E155G) Ca2+ binding motifs. We found that all GCAP1 variants form relatively stable dimers showing decreased apparent affinity for Ca2+ and blocking the enzyme in a constitutively active state at physiological levels of Ca2+. Interestingly, by corroborating spectroscopic experiments with molecular dynamics simulations we show that beside local structural effects, mutation of the bidentate glutamate in an EF-hand calcium binding motif can profoundly perturb the flexibility of the adjacent EF-hand as well, ultimately destabilizing the whole domain. Therefore, while Ca2+-binding to GCAP1 per se occurs sequentially, allosteric effects may connect EF hand motifs, which appear to be essential for the integrity of the structural switch mechanism in GCAP1, and perhaps in other NCS proteins.	Jul 2020
I04-Macromolecular Crystallography	High-resolution crystal structure of gelsolin domain 2 in complex with the physiological calcium ion Michela Bollati , Emanuele Scalone , Francesco Boni , Eloise Mastrangelo , Toni Giorgino , Mario Milani , Matteo De Rosa Biochemical And Biophysical Research Communications DOI: 10.1016/j.bbrc.2019.08.013 Diamond Proposal Number(s): [20221] Show Abstract ▼ 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.	Aug 2019

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