|
|
Nicholas
Favalli
,
Gabriele
Bassi
,
Christian
Pellegrino
,
Jacopo
Millul
,
Roberto
De Luca
,
Samuele
Cazzamalli
,
Su
Yang
,
Anika
Trenner
,
Nour L.
Mozaffari
,
Renier
Myburgh
,
Mustafa
Moroglu
,
Stuart J.
Conway
,
Alessandro A.
Sartori
,
Markus G.
Manz
,
Richard A.
Lerner
,
Peter K.
Vogt
,
Jörg
Scheuermann
,
Dario
Neri
Abstract: The encoding of chemical compounds with amplifiable DNA tags facilitates the discovery of small-molecule ligands for proteins. To investigate the impact of stereo- and regiochemistry on ligand discovery, we synthesized a DNA-encoded library of 670,752 derivatives based on 2-azido-3-iodophenylpropionic acids. The library was selected against multiple proteins and yielded specific ligands. The selection fingerprints obtained for a set of protein targets of pharmaceutical relevance clearly showed the preferential enrichment of ortho-, meta- or para-regioisomers, which was experimentally verified by affinity measurements in the absence of DNA. The discovered ligands included novel selective enzyme inhibitors and binders to tumour-associated antigens, which enabled conditional chimeric antigen receptor T-cell activation and tumour targeting.
|
Apr 2021
|
|
I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
|
Diamond Proposal Number(s):
[12342, 23269]
Open Access
Abstract: The rational design of linear peptides that assemble controllably and predictably in water is challenging. Short sequences must encode unique target structures and avoid alternative states. However, the non-covalent forces that stabilize and discriminate between states are weak. Nonetheless, for α-helical coiled-coil assemblies considerable progress has been made in rational de novo design. In these, sequence repeats of nominally hydrophobic (h) and polar (p) residues, hpphppp, direct the assembly of amphipathic helices into dimeric to tetrameric bundles. Expanding this pattern to hpphhph can produce larger α-helical barrels. Here, we show that pentameric to nonameric barrels are accessed by varying the residue at one of the h sites. In peptides with four L/I–K–E–I–A–x–Z repeats, decreasing the size of Z from threonine to serine to alanine to glycine gives progressively larger oligomers. X-ray crystal structures of the resulting α-helical barrels rationalize this: side chains at Z point directly into the helical interfaces, and smaller residues allow closer helix contacts and larger assemblies.
|
Apr 2021
|
|
|
|
Hanna
Kwon
,
Jaswir
Basran
,
Chinar
Pathak
,
Mahdi
Hussain
,
Samuel L.
Freeman
,
Alistair J.
Fielding
,
Anna J.
Bailey
,
Natalia
Stefanou
,
Hazel A.
Sparkes
,
Takehiko
Tosha
,
Keitaro
Yamashita
,
Kunio
Hirata
,
Hironori
Murakami
,
Go
Ueno
,
Hideo
Ago
,
Kensuke
Tono
,
Masaki
Yamamoto
,
Hitomi
Sawai
,
Yoshitsugu
Shiro
,
Hiroshi
Sugimoto
,
Emma
Raven
,
Peter C. E.
Moody
Abstract: Oxygen activation in all heme enzymes requires the formation of high oxidation states of iron, usually referred to as ferryl heme. There are two known intermediates: Compound I and Compound II. The nature of the ferryl heme – and whether it is an Fe IV =O or Fe IV ‐OH species – is important for controlling reactivity across groups of heme enzymes. The most recent evidence for Compound I indicates that the ferryl heme is an unprotonated Fe IV =O species. For Compound II, the nature of the ferryl heme is not unambiguously established. Here, we report 1.06 Å and 1.50 Å crystal structures for Compound II intermediates in cytochrome c peroxidase (C c P) and ascorbate peroxidase (APX), collected using the X‐ray free electron laser at SACLA. The structures reveal differences between the two peroxidases. The iron‐oxygen bond length in C c P (1.76 Å) is notably shorter than in APX (1.87 Å). The results indicate that the ferryl species is finely tuned across Compound I and Compound II species in closely related peroxidase enzymes. We propose that this fine‐tuning is linked to the functional need for proton delivery to the heme.
|
Apr 2021
|
|
I04-Macromolecular Crystallography
|
Abstract: Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite (Plasmodium falciparum) lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with in vitro pharmacokinetics. Co-crystallization of the most potent compound in our series (CL-2) with PfKRS revealed its structural basis of enzymatic binding and potency. Further, we report that CL-2 has performed better than cladosporin in terms of metabolic stability. It thus represents a new lead for further optimization toward the development of antimalarial drugs. Collectively, along with a lead compound, the series offers insights on how even the slightest chemical modification might play an important role in enhancing or decreasing the potency of a chemical scaffold.
|
Apr 2021
|
|
I24-Microfocus Macromolecular Crystallography
|
Stefano
De Benedetti
,
Flavio
Di Pisa
,
Enrico Mario Alessandro
Fassi
,
Marina
Cretich
,
Angelo
Musicò
,
Roberto
Frigerio
,
Alessandro
Mussida
,
Mauro
Bombaci
,
Renata
Grifantini
,
Giorgio
Colombo
,
Martino
Bolognesi
,
Romualdo
Grande
,
Nadia
Zanchetta
,
Maria Rita
Gismondo
,
Davide
Mileto
,
Alessandro
Mancon
,
Louise Jane
Gourlay
Diamond Proposal Number(s):
[5912]
Open Access
Abstract: The human parasitic disease Schistosomiasis is caused by the Schistosoma trematode flatworm that infects freshwaters in tropical regions of the world, particularly in Sub-Saharan Africa, South America, and the Far-East. It has also been observed as an emerging disease in Europe, due to increased immigration. In addition to improved therapeutic strategies, it is imperative to develop novel, rapid, and sensitive diagnostic tests that can detect the Schistosoma parasite, allowing timely treatment. Present diagnosis is difficult and involves microscopy-based detection of Schistosoma eggs in the feces. In this context, we present the 3.22 Å resolution crystal structure of the circulating antigen Serine protease inhibitor from S. mansoni (SmSPI), and we describe it as a potential serodiagnostic marker. Moreover, we identify three potential immunoreactive epitopes using in silico-based epitope mapping methods. Here, we confirm effective immune sera reactivity of the recombinant antigen, suggesting the further investigation of the protein and/or its predicted epitopes as serodiagnostic Schistosomiasis biomarkers.
|
Apr 2021
|
|
I04-1-Macromolecular Crystallography (fixed wavelength)
|
Open Access
Abstract: We have developed a high‐throughput system to synthesise and explore up to 96 heterogeneous catalysts at the same time. The system was developed as a proof of concept, using a standard glass plate and a 3D printed 96‐well plate. Nano‐droplets of catalyst formulations were transferred to the glass plate using an acoustic liquid handler and upon heat treatments, the miniature mesoporous metal oxide (MMO) catalysts were formed. The 3D printed bottomless 96‐well plate was fixed to the glass plate, to give 96 individual wells, each containing a catalyst. Four catalyst plates were prepared (Co3O4‐, Au/Co3O4‐, Pd/Co3O4‐ and Co/Mn‐MMO) to be screened for their activity in the oxidation of morin, as a model reaction. The observed reaction rates (kobs) for each catalyst were calculated to identify the most active catalyst. The general method described herein requires microscopic amounts of catalysts with derivates of the catalyst's composition.
|
Apr 2021
|
|
I16-Materials and Magnetism
|
Hiroki
Ueda
,
Michael
Porer
,
Jose R. L.
Mardegan
,
Sergii
Parchenko
,
Namrata
Gurung
,
Federica
Fabrizi
,
Mahesh
Ramakrishnan
,
Larissa
Boie
,
Martin Josef
Neugebauer
,
Bulat
Burganov
,
Max
Burian
,
Steven Lee
Johnson
,
Kai
Rossnagel
,
Urs
Staub
Diamond Proposal Number(s):
[15742]
Open Access
Abstract: The correlation between electronic and crystal structures of
1T − TiSe2
in the charge-density wave (CDW) state is studied by x-ray diffraction in order to clarify basic properties in the CDW state, transport properties, and chirality. Three families of reflections are used to probe atomic displacements and the orbital asymmetry in Se. Two distinct onset temperatures are found:
T
CDW
and a lower
T
∗
indicative for an onset of Se out-of-plane atomic displacements.
T
∗
coincides with a DC resistivity maximum and the onset of the proposed gyrotropic (chiral) electronic structure. However, no indication for chirality is found. The relation between the atomic displacements and the transport properties is discussed in terms of Ti
3
d
and Se
4
p
states that only weakly couple to the CDW order.
|
Apr 2021
|
|
I11-High Resolution Powder Diffraction
|
Abstract: While Ti-Nb binary alloys have been extensively studied over the years, there are discrepancies in the literature relating to the β-α″ martensitic transformation that indicate an incomplete understanding. In particular, there are inconsistencies regarding the phase constitution of as-quenched material and the ability for α″ phase to be thermally-induced. To resolve these issues, the β-α″ phase transformation is studied in a Ti-24Nb (at.%) alloy subjected to two different water quench conditions. It is demonstrated that only the fastest quench rates (≳500˚C/s) result in the formation of α″ phase, and these materials exhibit a reversible thermally-induced β-α″ transformation at low temperatures. In contrast, slightly slower water quench procedures lead to a β+ω microstructure, and these samples do not exhibit a thermally-induced β-α″ transformation, even when cooled to -168˚C. Despite this, room temperature mechanical testing results indicate that α″ can be induced by stresses as low as 200 MPa. To explain these results, it is proposed that quenching stresses play a role in the competition between α″ and athermal ω phases at rapid quench rates. The present results are then reconciled with the body of literature and a broader understanding of phase stability in metastable β-titanium alloys.
|
Apr 2021
|
|
I12-JEEP: Joint Engineering, Environmental and Processing
|
Chi Ming
Yim
,
Soumendra Nath
Panja
,
Christopher
Trainer
,
Craig
Topping
,
Christoph
Heil
,
Alexandra S.
Gibbs
,
Oxana
Magdysyuk
,
Vladimir
Tsurkan
,
Alois
Loidl
,
Andreas W.
Rost
,
Peter
Wahl
Diamond Proposal Number(s):
[22974]
Open Access
Abstract: A key property of many quantum materials is that their ground state depends sensitively on small changes of an external tuning parameter, e.g., doping, magnetic field, or pressure, creating opportunities for potential technological applications. Here, we explore tuning of the ground state of the nonsuperconducting parent compound, Fe1+xTe, of the iron chalcogenides by uniaxial strain. Iron telluride exhibits a peculiar (π, 0) antiferromagnetic order unlike the (π, π) order observed in the Fe-pnictide superconductors. The (π, 0) order is accompanied by a significant monoclinic distortion. We explore tuning of the ground state by uniaxial strain combined with low-temperature scanning tunneling microscopy. We demonstrate that, indeed under strain, the surface of Fe1.1Te undergoes a transition to a (π, π)-charge-ordered state. Comparison with transport experiments on uniaxially strained samples shows that this is a surface phase, demonstrating the opportunities afforded by 2D correlated phases stabilized near surfaces and interfaces.
|
Apr 2021
|
|
I19-Small Molecule Single Crystal Diffraction
|
Diamond Proposal Number(s):
[8682]
Abstract: Herein we present a rearomative diastereoselective etherification/amination reaction of 2,3,9,9a-tetrahydro-
1H-carbazoles, themselves accessible via the Diels-Alder reaction of N-protected 3-vinyl-1H-indoles. We
have developed a one-pot rearomative bromination/nucleophilic substitution reaction sequence employing both
O- and N-centred nucleophiles, inverting the typical reactivity of 2,3,9,9a-tetrahydro-1H-carbazoles at the
4-position. Alcohols or secondary amines can be incorporated allowing access to the corresponding 4-substituted-
2,3,4,9-tetrahydro-1H-carbazoles, the diastereoselectivity of the reaction being controlled by the nature of
the nucleophile and the reaction conditions.
|
Apr 2021
|
|
