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82 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I24-Microfocus Macromolecular Crystallography	The structural basis of fatty acid elongation by the ELOVL elongases Laiyin Nie , Tomas C. Pascoa , Ashley C. W. Pike , Simon R. Bushell , Andrew Quigley , Gian Filippo Ruda , Amy Chu , Victoria Cole , David Speedman , Tiago Moreira , Leela Shrestha , Shubhashish M. M. Mukhopadhyay , Nicola A. Burgess-Brown , James D. Love , Paul E. Brennan , Elisabeth P. Carpenter Nature Structural & Molecular Biology 28, 512 - 520 DOI: 10.1038/s41594-021-00605-6 Diamond Proposal Number(s): [19301] Show Abstract ▼ Abstract: Very long chain fatty acids (VLCFAs) are essential building blocks for the synthesis of ceramides and sphingolipids. The first step in the fatty acid elongation cycle is catalyzed by the 3-keto acyl-coenzyme A (CoA) synthases (in mammals, ELOVL elongases). Although ELOVLs are implicated in common diseases, including insulin resistance, hepatic steatosis and Parkinson’s, their underlying molecular mechanisms are unknown. Here we report the structure of the human ELOVL7 elongase, which comprises an inverted transmembrane barrel surrounding a 35-Å long tunnel containing a covalently attached product analogue. The structure reveals the substrate-binding sites in the narrow tunnel and an active site deep in the membrane. We demonstrate that chain elongation proceeds via an acyl-enzyme intermediate involving the second histidine in the canonical HxxHH motif. The unusual substrate-binding arrangement and chemistry suggest mechanisms for selective ELOVL inhibition, relevant for diseases where VLCFAs accumulate, such as X-linked adrenoleukodystrophy.	Jun 2021
	Making the invisible enemy visible Tristan I. Croll , Kay Diederichs , Florens Fischer , Cameron D. Fyfe , Yunyun Gao , Sam Horrell , Agnel Praveen Joseph , Luise Kandler , Oliver Kippes , Ferdinand Kirsten , Konstantin Müller , Kristopher Nolte , Alexander M. Payne , Matthew Reeves , Jane S. Richardson , Gianluca Santoni , Sabrina Stäb , Dale E. Tronrud , Lea C. Von Soosten , Christopher J. Williams , Andrea Thorn Nature Structural & Molecular Biology 28, 404 - 408 DOI: 10.1038/s41594-021-00593-7 Show Abstract ▼ Abstract: Structural biology plays a crucial role in the fight against COVID-19, permitting us to ‘see’ and understand SARS-CoV-2. However, the macromolecular structures of SARS-CoV-2 proteins that were solved with great speed and urgency can contain errors that may hinder drug design. The Coronavirus Structural Task Force has been working behind the scenes to evaluate and improve these structures, making the results freely available at https://insidecorona.net/.	May 2021
B21-High Throughput SAXS I04-Macromolecular Crystallography	Structural basis of FANCD2 deubiquitination by USP1−UAF1 Martin L. Rennie , Connor Arkinson , Viduth K. Chaugule , Rachel Toth , Helen Walden Nature Structural & Molecular Biology 18 DOI: 10.1038/s41594-021-00576-8 Diamond Proposal Number(s): [14980, 19844] Show Abstract ▼ Abstract: Ubiquitin-specific protease 1 (USP1) acts together with the cofactor UAF1 during DNA repair processes to specifically remove monoubiquitin signals. One substrate of the USP1−UAF1 complex is the monoubiquitinated FANCI−FANCD2 heterodimer, which is involved in the repair of DNA interstrand crosslinks via the Fanconi anemia pathway. Here we determine structures of human USP1−UAF1 with and without ubiquitin and bound to monoubiquitinated FANCI−FANCD2. The crystal structures of USP1−UAF1 reveal plasticity in USP1 and key differences to USP12−UAF1 and USP46−UAF1, two related proteases. A cryo-EM reconstruction of USP1−UAF1 in complex with monoubiquitinated FANCI−FANCD2 highlights a highly orchestrated deubiquitination process, with USP1−UAF1 driving conformational changes in the substrate. An extensive interface between UAF1 and FANCI, confirmed by mutagenesis and biochemical assays, provides a molecular explanation for the requirement of both proteins, despite neither being directly involved in catalysis. Overall, our data provide molecular details of USP1−UAF1 regulation and substrate recognition.	Apr 2021
Krios I-Titan Krios I at Diamond Krios III-Titan Krios III at Diamond	Mechanism of auto-inhibition and activation of Mec1ATR checkpoint kinase Elias A. Tannous , Luke A. Yates , Xiaodong Zhang , Peter M. Burgers Nature Structural & Molecular Biology 149 DOI: 10.1038/s41594-020-00522-0 Diamond Proposal Number(s): [19865] Show Abstract ▼ Abstract: In response to DNA damage or replication fork stalling, the basal activity of Mec1ATR is stimulated in a cell-cycle-dependent manner, leading to cell-cycle arrest and the promotion of DNA repair. Mec1ATR dysfunction leads to cell death in yeast and causes chromosome instability and embryonic lethality in mammals. Thus, ATR is a major target for cancer therapies in homologous recombination–deficient cancers. Here we identify a single mutation in Mec1, conserved in ATR, that results in constitutive activity. Using cryo-electron microscopy, we determine the structures of this constitutively active form (Mec1(F2244L)-Ddc2) at 2.8 Å and the wild type at 3.8 Å, both in complex with Mg2+-AMP-PNP. These structures yield a near-complete atomic model for Mec1–Ddc2 and uncover the molecular basis for low basal activity and the conformational changes required for activation. Combined with biochemical and genetic data, we discover key regulatory regions and propose a Mec1 activation mechanism.	Nov 2020
Krios I-Titan Krios I at Diamond Krios IV-Titan Krios IV at Diamond	Intrinsic curvature of the HIV-1 CA hexamer underlies capsid topology and interaction with cyclophilin A Tao Ni , Samuel Gerard , Gongpu Zhao , Kyle Dent , Jiying Ning , Jing Zhou , Jiong Shi , Jordan Anderson-Daniels , Wen Li , Sooin Jang , Alan N. Engelman , Christopher Aiken , Peijun Zhang Nature Structural & Molecular Biology 5 DOI: 10.1038/s41594-020-0467-8 Diamond Proposal Number(s): [14856, 21004] Show Abstract ▼ Abstract: The mature retrovirus capsid consists of a variably curved lattice of capsid protein (CA) hexamers and pentamers. High-resolution structures of the curved assembly, or in complex with host factors, have not been available. By devising cryo-EM methodologies for exceedingly flexible and pleomorphic assemblies, we have determined cryo-EM structures of apo-CA hexamers and in complex with cyclophilin A (CypA) at near-atomic resolutions. The CA hexamers are intrinsically curved, flexible and asymmetric, revealing the capsomere and not the previously touted dimer or trimer interfaces as the key contributor to capsid curvature. CypA recognizes specific geometries of the curved lattice, simultaneously interacting with three CA protomers from adjacent hexamers via two noncanonical interfaces, thus stabilizing the capsid. By determining multiple structures from various helical symmetries, we further revealed the essential plasticity of the CA molecule, which allows formation of continuously curved conical capsids and the mechanism of capsid pattern sensing by CypA.	Aug 2020
Krios IV-Titan Krios IV at Diamond	Mitochondrial complex I structure reveals ordered water molecules for catalysis and proton translocation Daniel Grba , Judy Hirst Nature Structural & Molecular Biology 82 DOI: 10.1038/s41594-020-0473-x Diamond Proposal Number(s): [17057] Show Abstract ▼ Abstract: Mitochondrial complex I powers ATP synthesis by oxidative phosphorylation, exploiting the energy from ubiquinone reduction by NADH to drive protons across the energy-transducing inner membrane. Recent cryo-EM analyses of mammalian and yeast complex I have revolutionized structural and mechanistic knowledge and defined structures in different functional states. Here, we describe a 2.7-Å-resolution structure of the 42-subunit complex I from the yeast Yarrowia lipolytica containing 275 structured water molecules. We identify a proton-relay pathway for ubiquinone reduction and water molecules that connect mechanistically crucial elements and constitute proton-translocation pathways through the membrane. By comparison with known structures, we deconvolute structural changes governing the mammalian ‘deactive transition’ (relevant to ischemia–reperfusion injury) and their effects on the ubiquinone-binding site and a connected cavity in ND1. Our structure thus provides important insights into catalysis by this enigmatic respiratory machine.	Aug 2020
I03-Macromolecular Crystallography Krios I-Titan Krios I at Diamond	Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2 Jiangdong Huo , Audrey Le Bas , Reinis R. Ruza , Helen M. E. Duyvesteyn , Halina Mikolajek , Tomas Malinauskas , Tiong Kit Tan , Pramila Rijal , Maud Dumoux , Philip N. Ward , Jingshan Ren , Daming Zhou , Peter J. Harrison , Miriam Weckener , Daniel K. Clare , Vinod K. Vogirala , Julika Radecke , Lucile Moynie , Yuguang Zhao , Javier Gilbert-Jaramillo , Michael L. Knight , Julia A. Tree , Karen R. Buttigieg , Naomi Coombes , Michael J. Elmore , Miles W. Carroll , Loic Carrique , Pranav N. M. Shah , William James , Alain R. Townsend , David I. Stuart , Raymond J. Owens , James H. Naismith Nature Structural & Molecular Biology 21 DOI: 10.1038/s41594-020-0469-6 Diamond Proposal Number(s): [27031, 27051] Open Access Show Abstract ▼ Abstract: The SARS-CoV-2 virus is more transmissible than previous coronaviruses and causes a more serious illness than influenza. The SARS-CoV-2 receptor binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor as a prelude to viral entry into the cell. Using a naive llama single-domain antibody library and PCR-based maturation, we have produced two closely related nanobodies, H11-D4 and H11-H4, that bind RBD (KD of 39 and 12 nM, respectively) and block its interaction with ACE2. Single-particle cryo-EM revealed that both nanobodies bind to all three RBDs in the spike trimer. Crystal structures of each nanobody–RBD complex revealed how both nanobodies recognize the same epitope, which partly overlaps with the ACE2 binding surface, explaining the blocking of the RBD–ACE2 interaction. Nanobody-Fc fusions showed neutralizing activity against SARS-CoV-2 (4–6 nM for H11-H4, 18 nM for H11-D4) and additive neutralization with the SARS-CoV-1/2 antibody CR3022.	Jul 2020
I03-Macromolecular Crystallography Krios I-Titan Krios I at Diamond	Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient Daming Zhou , Helen M. E. Duyvesteyn , Cheng-Pin Chen , Chung-Guei Huang , Ting-Hua Chen , Shin-Ru Shih , Yi-Chun Lin , Chien-Yu Cheng , Shu-Hsing Cheng , Yhu-Chering Huang , Tzou-Yien Lin , Che Ma , Jiandong Huo , Loic Carrique , Tomas Malinauskas , Reinis R. Ruza , Pranav Shah , Tiong Kit Tan , Pramila Rijal , Robert F. Donat , Kerry Godwin , Karen R. Buttigieg , Julia A. Tree , Julika Radecke , Neil Paterson , Piyada Supasa , Juthathip Mongkolsapaya , Gavin R. Screaton , Miles W. Carroll , Javier Gilbert-Jaramillo , Michael L. Knight , William James , Raymond J. Owens , James H. Naismith , Alain R. Townsend , Elizabeth E. Fry , Yuguang Zhao , Jingshan Ren , David I. Stuart , Kuan-Ying A. Huang Nature Structural & Molecular Biology 20 DOI: 10.1038/s41594-020-0480-y Diamond Proposal Number(s): [19946, 26983] Show Abstract ▼ Abstract: The COVID-19 pandemic has had an unprecedented health and economic impact and there are currently no approved therapies. We have isolated an antibody, EY6A, from an individual convalescing from COVID-19 and have shown that it neutralizes SARS-CoV-2 and cross-reacts with SARS-CoV-1. EY6A Fab binds the receptor binding domain (RBD) of the viral spike glycoprotein tightly (KD of 2 nM), and a 2.6-Å-resolution crystal structure of an RBD–EY6A Fab complex identifies the highly conserved epitope, away from the ACE2 receptor binding site. Residues within this footprint are key to stabilizing the pre-fusion spike. Cryo-EM analyses of the pre-fusion spike incubated with EY6A Fab reveal a complex of the intact spike trimer with three Fabs bound and two further multimeric forms comprising the destabilized spike attached to Fab. EY6A binds what is probably a major neutralizing epitope, making it a candidate therapeutic for COVID-19.	Jul 2020
Krios I-Titan Krios I at Diamond	Cryo-EM structures of holo condensin reveal a subunit flip-flop mechanism Byung-Gil Lee , Fabian Merkel , Matteo Allegretti , Markus Hassler , Christopher Cawood , Léa Lecomte , Francis J. O'Reilly , Ludwig R. Sinn , Pilar Gutierrez-Escribano , Marc Kschonsak , Sol Bravo , Takanori Nakane , Juri Rappsilber , Luis Aragon , Martin Beck , Jan Lowe , Christian H. Haering Nature Structural & Molecular Biology 53 DOI: 10.1038/s41594-020-0457-x Show Abstract ▼ Abstract: Complexes containing a pair of structural maintenance of chromosomes (SMC) family proteins are fundamental for the three-dimensional (3D) organization of genomes in all domains of life. The eukaryotic SMC complexes cohesin and condensin are thought to fold interphase and mitotic chromosomes, respectively, into large loop domains, although the underlying molecular mechanisms have remained unknown. We used cryo-EM to investigate the nucleotide-driven reaction cycle of condensin from the budding yeast Saccharomyces cerevisiae. Our structures of the five-subunit condensin holo complex at different functional stages suggest that ATP binding induces the transition of the SMC coiled coils from a folded-rod conformation into a more open architecture. ATP binding simultaneously triggers the exchange of the two HEAT-repeat subunits bound to the SMC ATPase head domains. We propose that these steps result in the interconversion of DNA-binding sites in the catalytic core of condensin, forming the basis of the DNA translocation and loop-extrusion activities.	Jul 2020
I03-Macromolecular Crystallography	An embedded lipid in the multidrug transporter LmrP suggests a mechanism for polyspecificity Vincent Debruycker , Andrew Hutchin , Matthieu Masureel , Emel Ficici , Chloé Martens , Pierre Legrand , Richard A. Stein , Hassane S. Mchaourab , José D. Faraldo-Gómez , Han Remaut , Cedric Govaerts Nature Structural & Molecular Biology 10 DOI: 10.1038/s41594-020-0464-y Diamond Proposal Number(s): [12718] Show Abstract ▼ Abstract: Multidrug efflux pumps present a challenge to the treatment of bacterial infections, making it vitally important to understand their mechanism of action. Here, we investigate the nature of substrate binding within Lactococcus lactis LmrP, a prototypical multidrug transporter of the major facilitator superfamily. We determined the crystal structure of LmrP in a ligand-bound outward-open state and observed an embedded lipid in the binding cavity of LmrP, an observation supported by native mass spectrometry analyses. Molecular dynamics simulations suggest that the anionic lipid stabilizes the observed ligand-bound structure. Mutants engineered to disrupt binding of the embedded lipid display reduced transport of some, but not all, antibiotic substrates. Our results suggest that a lipid within the binding cavity could provide a malleable hydrophobic component that allows adaptation to the presence of different substrates, helping to explain the broad specificity of this protein and possibly other multidrug transporters.	Jul 2020

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