Krios III-Titan Krios III at Diamond
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Jesper S.
Hansen
,
Ashley C. W.
Pike
,
Gamma
Chi
,
Gernot
Wolf
,
Jeppe
Tranberg-Jensen
,
Hannah
Lichtmannegger
,
David
Speedman
,
Alvaro
Ingles-Prieto
,
Fabian
Goericke
,
Helena
Batoulis
,
Hartmut
Beck
,
Rajini
Rao
,
Tooraj
Mirshahi
,
David B.
Sauer
,
Giulio
Superti-Furga
,
Kilian V. M.
Huber
Diamond Proposal Number(s):
[28713]
Open Access
Abstract: Endosomal NHE6 (SLC9A6) and NHE9 (SLC9A9) transporters are essential for maintaining pH homeostasis within endosomes and their dysfunction has been linked to neurological and neurodegenerative disorders. NHE6 and NHE9 are widely considered to function as electroneutral exchangers that couple the export of protons to the import of sodium or potassium ions across cellular membranes, thereby forming the basis of proton leak pathways for internal pH balancing and fine-tuning. Among the 13 identified SLC9 family members, only NHE6 and NHE9 are targeted to endosomes. Despite their biological importance and therapeutic potential, the structural basis for their activity and regulation remains elusive. Here, we present the cryo-EM structures of human NHE9 and two splice variants of NHE6 that differ by alternative inclusion of the β-hairpin motif-containing loop domain located between transmembrane helices 2 and 3, showcasing structural diversity within the organellar NHE subfamily. By mapping the sodium-binding site, our results provide mechanistic insights into ion transport, and for NHE6 we provide evidence for a conserved PIP2-mediated regulatory mechanism. These findings provide a framework for understanding endosomal NHE function with implications for disorders such as Alzheimer’s disease and glioblastoma.
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Sep 2026
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I20-Scanning-X-ray spectroscopy (XAS/XES)
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Filip J. R.
Meysman
,
Bent
Smets
,
Silvia
Hidalgo-Martinez
,
Nathalie
Claes
,
Bob C.
Schroeder
,
Jeanine S.
Geelhoed
,
Yun
Liu
,
Jiji
Alingapoyil Choyikutty
,
Tamazouzt
Chennit
,
Thijs
Bodson
,
Alberto
Collauto
,
Maxie M.
Roessler
,
Dmitry
Karpov
,
Sylvain
Bohic
,
Matteo
Aramini
,
Shusaku
Hayama
,
Maxwell
Wetherington
,
Martijn A.
Zwijnenburg
,
Galina
Pankratova
,
Isabel
Pintelon
,
Jean-Pierre
Timmermans
,
Gert
Nuyts
,
Karolien
De Wael
,
Sara
Bals
,
Jo
Verbeeck
,
Han
Remaut
,
Henricus T. S.
Boschker
Diamond Proposal Number(s):
[31284, 36538, 38275]
Open Access
Abstract: Biobased electronics aims for disruptive innovation in sustainable electronics but is obstructed by the low intrinsic conductivity of biomaterials. Recently, fibres were discovered within the cell envelope of multi-cellular cable bacteria, which display an exceptional conductivity for a biomaterial. Yet, the molecular structure and electron transport mechanism remain unresolved, thus precluding a detailed structure-function understanding and the development of biomimetic analogues. Here, we demonstrate that each fibre embeds an extended nickel-organic framework, which consists of a bundle of intertwined nanoribbons, each built from stacked repeat units in which multiple nickel centres are linked by organic dithiolene ligands. This metal-organic supramolecular architecture provides extensive conjugation and electron delocalization, thus enabling exceptional conductance over macroscale distances. This suggests a novel design principle for bio-based electronic materials and opens possibilities for biosynthesis of metal-organic frameworks.
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Sep 2026
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Krios I-Titan Krios I at Diamond
Krios IV-Titan Krios IV at Diamond
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Yasunori
Noguchi
,
Almutasem
Saleh
,
Sarah
Schneider
,
Marina E.
Ivanova
,
Zhuo Angel
Chen
,
Lepakshi
Ranjha
,
Ricardo
Aramayo
,
Silvia
Tognetti
,
Sarah V.
Faull
,
Juri
Rappsilber
,
Christian
Speck
Diamond Proposal Number(s):
[25127, 18659]
Open Access
Abstract: Regulated helicase activation by DDK kinase is central for genome stability. However, how DDK phosphorylation primes the MCM2-7 double hexamer (DH) for Sld3-Sld7 binding and Cdc45 loading remained unclear. We define this mechanism through cryo-EM structures of MCM2-7 DH-Sld3-Sld7 (MS) and MCM2-7 DH-Sld3-Sld7-Cdc45 (MSC). We reveal that the autoinhibitory Mcm4 tail engages not only Mcm4 but also Mcm6. Upon DDK-dependent phosphorylation, both of these sites become accessible. In the context of the MS structure, we identify that two short Sld3 motifs that contact Mcm4 and Mcm6 read out the DH phosphorylation state, while the Sld3 Treslin domain (STD) binds to Mcm2. In the MSC structure, Cdc45 dislodges the Sld3 STD from Mcm2, allowing Sld3 to position Cdc45 at the Mcm2/Mcm5 interface. Mutagenesis of the Sld3 STD-Cdc45 interface disrupts Cdc45 loading, validating this interaction. Together, our data reveal a phosphorylation-encoded mechanism coupling DDK-activated Mcm4/Mcm6 surfaces to distal Cdc45 placement, explaining how firing factors choreograph the DH-to-CMG transition.
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Aug 2026
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I04-Macromolecular Crystallography
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Dustin A.
Ammendolia
,
Cara J.
Ellison
,
Yuelin
Zheng
,
Etienne
Coyaud
,
Estelle M. N.
Laurent
,
Bing-Ru
Yan
,
Bri
Manning
,
Anna K.
Waldmann
,
Joel M. J.
Tan
,
Scott
Frendo-Cumbo
,
Carina
Lyons
,
Ji-Young
Youn
,
Brian
Raught
,
Keith
Ireton
,
Darren E.
Higgins
,
Paul R.
Elliott
,
John H.
Brumell
Open Access
Abstract: Listeria monocytogenes (Lm) is an intracellular pathogen that can cause life-threatening systemic infections. Internalin C (InlC) is a secreted factor required for full Lm virulence in systemic models of infection by mechanisms that remain unclear. Here, we show that InlC binds to CYLD, a host deubiquitinase and regulator of innate immunity. Structurally, we reveal the LRR domain of InlC binds the CAP-Gly2 domain of CYLD, independently of InlC’s binding site for other host target proteins. Lm strains harboring amino acid substitutions in InlC that selectively disrupt binding to CYLD were examined. We demonstrate that after Lm accesses the host cytosol, InlC recruits CYLD to ubiquitin-positive bacteria. Recruitment of CYLD was dependent on the host E3 ligase RNF213, a major initiator of ubiquitin-mediated defenses. Furthermore, InlC-CYLD binding contributed to Lm virulence in mice. Together, these findings reveal how a secreted bacterial factor promotes the recruitment of a host deubiquitinase to cytosolic bacteria in response to ubiquitin-mediated defenses.
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Aug 2026
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I03-Macromolecular Crystallography
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Diamond Proposal Number(s):
[38021]
Open Access
Abstract: Enzymes that catalyze non-natural C–C bond-forming reactions are powerful tools in asymmetric synthesis, yet reprogramming their active sites to invert stereochemical outcome remains challenging. Building on our recently engineered SNArase, SNAr1.3, which performs enantioselective nucleophilic aromatic substitutions with carbon nucleophiles, we now report the evolution of an enantiocomplementary biocatalyst (eSNAr1.3) that displays enhanced activity and expanded substrate scope. Structural and computational analyses uncover both conserved and divergent features between SNAr1.3 and eSNAr1.3. Despite retaining similar electrophile binding poses and a conserved catalytic arginine, the halide-binding pocket of SNAr1.3 has been abandoned in eSNAr1.3. Instead, His23 has emerged as a key motif that works with Arg124 to accurately position the nucleophilic substrate. Calculations reveal that Arg124 also plays a crucial role in facilitating halide release during catalysis. Our study demonstrates how evolution can reshape enzyme mechanisms in unforeseen ways, highlighting the importance of exploring diverse trajectories to access new functions.
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Aug 2026
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Krios I-Titan Krios I at Diamond
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Stephanie A.
Nestorow
,
Wan-Na
Chen
,
Daniel
Bertrand
,
Ayla A.
Wahid
,
Caroline E.
Wyatt
,
Martin
Mortensen
,
Thomas
Clairfeuille
,
Michael
Reutlinger
,
Gregoire
Friz
,
Els
Pardon
,
Jan
Steyaert
,
Graham
Ladds
,
Giuseppe
Cecere
,
Trevor G.
Smart
,
Maria-Clemencia
Hernandez
,
Lisa
Joedicke
,
Paul S.
Miller
Diamond Proposal Number(s):
[37678]
Open Access
Abstract: γ-aminobutyric acid Type-A (GABAA) αβδ receptors regulate neuronal excitability and contribute to sleep, mood and motor coordination. However, the molecular arrangements of these receptors and the basis of GABA activation and δ-selective drug modulation remain unclear. We solve cryo-EM structures of α4β3δ receptors in an α-β-α-β-δ arrangement that contains two GABA binding pockets. GABA binding supports a classical β-subunit tilt and an outward configuration of the β-subunit M2-M3 loops. However, the δ subunit M2-M3 loop is orientated inward and the 9’ activation gate in the pore is closed, consistent with the low efficacy for these receptors. Addition of a δ-selective positive allosteric modulator (PAM), DS2-Me, reveals binding to an α-δ pocket that causes the 9’ activation gate to open. In this work we provide key insights into the stoichiometry, arrangement and molecular modes of GABA activation and δ-selective modulation of these critical regulators of neuronal excitability.
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Aug 2026
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I05-ARPES
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Cong
Li
,
Zhilong
Yang
,
Hongxiong
Liu
,
Magnus H.
Berntsen
,
Francesco
Scali
,
Dibya
Phuyal
,
Jianfeng
Zhang
,
Timur K.
Kim
,
Jacek
Osiecki
,
Balasubramanian
Thiagarajan
,
Youguo
Shi
,
Tao
Xiang
,
Quansheng
Wu
,
Oscar
Tjernberg
Diamond Proposal Number(s):
[39652, 41048]
Open Access
Abstract: Topological materials are defined by the correspondence between bulk topology and boundary states, yet this correspondence becomes enigmatic on low-symmetry surfaces where bulk and surface periodicities may not coincide within a conventional first bulk Brillouin zone projection. Here we study the (103) surface of the Weyl semimetal NdAlSi and identify Fermi arc interference in the boundary spectrum. Angle-resolved photoemission spectroscopy uncovers loop-like Fermi-arc connectivity and characteristic replica modulations that are not observed on high symmetry surfaces. Crucially, the topological surface states themselves are reconstructed because Fermi arcs from phase-shifted bulk-zone projections overlap and hybridize, producing connectivity patterns unique to low-symmetry facets. We show that these emerge from incomplete bulk projection and multi-cell interference governed by a least-common-multiple framework. Least-common-multiple guided density functional theory and Green’s-function calculations reproduce the reconstructed periodicity and dominant replica structure in the spectra, providing a broadly applicable commensuration guideline. These findings resolve the apparent bulk-boundary correspondence paradox on low-symmetry surfaces and provide an operational route to model and interpret boundary spectra on complex facets.
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Aug 2026
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I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Diamond Proposal Number(s):
[38144]
Open Access
Abstract: The PfPCRCR complex is essential for invasion of human erythrocytes by the deadliest malaria parasite, Plasmodium falciparum. Antibodies against each subunit of PfPCRCR prevent erythrocyte invasion and the PfRH5 component is currently the most advanced blood-stage malaria vaccine. Central within PfPCRCR is PfRIPR. This complex molecule contains a core and a flexible tail and allows PfPCRCR to bridge the parasite and erythrocyte during invasion. In this study, we generated a small panel of human monoclonal antibodies against PfRIPR. We structurally characterised four PfRIPR tail-binding antibodies in complex with PfRIPR fragments. We show that growth-inhibitory antibody RP.012 induces a kink in the PfRIPR tail while non-inhibitory antibodies do not. Furthermore, we show that these four antibodies modulate each other, either through antagonism or by acting synergistically. These studies have implications for the design of PfRIPR-based vaccine immunogens and indicate that the tail of PfRIPR undergoes essential conformational changes during erythrocyte invasion.
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Aug 2026
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B24-Cryo Soft X-ray Tomography
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Guiyu
Song
,
Zihan
Ma
,
Matthew
Fan
,
Liying
He
,
Yulong
Lan
,
Weihao
Li
,
Zhengtao
Jiang
,
Quan
Jiang
,
Dylan P.
Noone
,
Andrea
Nans
,
Kamal L.
Nahas
,
Mahsa Nouri
Barkestani
,
Shaoxun
Wang
,
Qianxun
Wang
,
Pengwei
Ren
,
Jolin
Cheng
,
Yinuo
Zang
,
Haitian
Zhou
,
Justin
Johnson
,
Clancy
Mullan
,
Xiangyu
Gong
,
Doryen
Bubeck
,
Gilbert
Moeckel
,
Michael
Mak
,
George
Tellides
,
Dan
Jane-Wit
Diamond Proposal Number(s):
[40765]
Open Access
Abstract: Immune effects of membrane attack complexes (MAC) have been widely attributed to their abilities to cause cell death. Here, we show that the MAC component, C9, forms non-cytolytic aggregates with pro-inflammatory effects. Intracellular aggregates of C9 are detected within inflamed tissues of patients in association with endothelial cell (EC) activation but not increased cell death. We identify NUMBL as a Rab35 effector that directly binds surface-bound C9 to promote C9 internalization and entry into the endolysosomal pathway. Within acidified endolysosomes, C9 forms insoluble aggregates that are targeted for degradative aggrephagy in a process that activates NF-κB. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates in vivo, and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-κB -dependent EC activation in three separate mouse models. Mice with conditional loss of ZFYVE21 in ECs show reduced aggregraphy, resulting in attenuated systemic inflammation and reduced tissue injury following skin transplantation. Our data show that the C9 component of MACs forms intracellular aggregates with alarmin-like properties.
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Jul 2026
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Roger B.
Dodd
,
Masahiro
Enomoto
,
Ye
Zhou
,
Kanayo
Satoh
,
Yalun
Zhang
,
Fusheng
Chen
,
Beatrice
Acheson
,
Deniz
Ghaffari
,
Elizabeth
Sayn-Wittgenstein
,
Jamie J.
Manning
,
George V.
Dukas
,
Ronak
Patel
,
Alondra Schweizer
Burguete
,
Mason J.
Kralovec
,
Mamunur
Rashid
,
Jennifer L.
Hall
,
Kirstin A.
Tamucci
,
Zena
Chatila
,
Minghua
Liu
,
Annie J.
Lee
,
Badri N.
Vardarajan
,
Mariko F.
Taga
,
Sirkku
Pollari
,
Alon
Rabinovitch
,
Cory D.
Rillahan
,
Andrey A.
Bobkov
,
Eduard
Sergienko
,
William
Meadows
,
Seema
Qamar
,
Suzanne J.
Randle
,
Christopher M.
Johnson
,
Jean
Sevalle
,
Jennifer
Griffin
,
Christopher
Bohm
,
Mitsuhiko
Ikura
,
Xunde
Xian
,
Joachim
Herz
,
Megan A.
Kelly
,
Jennifer
West
,
Sandeep
Satapathy
,
Mark R.
Wilson
,
Jonathan A.
Javitch
,
Paul E.
Fraser
,
David A.
Bennett
,
Philip L.
De Jager
,
Zvi
Fishelson
,
Dan
Frenkel
,
Wesley B.
Asher
,
Elizabeth M.
Bradshaw
,
Peter
St George-Hyslop
Diamond Proposal Number(s):
[8547]
Open Access
Abstract: Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33M splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33M ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33M, but not CD33m. We show that in human monocytes CD33M:CLU binding induces CD33M ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33M ectodomain fragment (sCD33M) - absent from CD33m-expressing cells - which could contribute to the role of CD33M in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33M axis, highlighting CD33M dimerization and ligand-binding sites as potential therapeutic targets.
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Jul 2026
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