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| Open AccessThe structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer
Here the authors describe multiple structures of the replicative helicase MCM2-7 in complex with Dbf4-dependent kinase (DDK). These structures reveal why the kinase specifically recognizes the MCM2-7 double-hexamer over the single-hexamer and explain how DDK can phosphorylate distantly located Mcm tails.
- Almutasem Saleh
- , Yasunori Noguchi
- & Christian Speck
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Article
| Open AccessTargeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer
The kinase DYRK2 is a known oncogene but its role in prostate cancer is unexplored. Here, the authors identify DYRK2 as a target for prostate cancer with a role in invasion and they discover a specific DYRK2 inhibitor that has good pharmacokinetics and efficacy in vivo.
- Kai Yuan
- , Zhaoxing Li
- & Peng Yang
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Article
| Open AccessVanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis
Cryo-EM often yields multiple protein conformations within a single dataset. Using the thermal titration methods and cryo-EM, Do Hoon Kwon et al. elucidate the conformational trajectory of the TRPV1 with resiniferatoxin (RTx) bound.
- Do Hoon Kwon
- , Feng Zhang
- & Seok-Yong Lee
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Article
| Open AccessMechanism of nucleotide discrimination by the translesion synthesis polymerase Rev1
Rev1 is a specialized translesion synthesis DNA polymerase involved in the bypass DNA damage during DNA replication. Here, the authors determine the structural basis for preferential incorporation of dCTP by Rev1 during bypass of DNA damage.
- Tyler M. Weaver
- , Timothy H. Click
- & Bret D. Freudenthal
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Article
| Open AccessThe unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands
The authors report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. The cryo-EM structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal different interaction modes and activation mechanisms of M4R. An antipsychotic activity of compound-110 with low extrapyramidal side effects in a schizophrenia-mimic mouse model is also reported. Thus, the study provides structural insights for selectively targeting mAChRs subtypes.
- Jingjing Wang
- , Meng Wu
- & Tian Hua
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Article
| Open AccessMolecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations
Ryanodine receptor 2 (RyR2) is a Ca2+ release channel essential for cardiac excitation-contraction coupling. Here, the authors use structural and functional analysis to reveal RyR2 gating mechanism and its alterations by pathogenic mutations.
- Takuya Kobayashi
- , Akihisa Tsutsumi
- & Haruo Ogawa
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Article
| Open AccessInsights into the client protein release mechanism of the ATP-independent chaperone Spy
How ATP-independent chaperones release their clients without energy input remains enigmatic. Here the authors discover that chaperone Spy uses its long, disordered N terminus to facilitate client release through competitive, dynamic intramolecular interactions with Spy’s client binding surface.
- Wei He
- , Xinming Li
- & Shu Quan
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Article
| Open AccessCodon-specific Ramachandran plots show amino acid backbone conformation depends on identity of the translated codon
Genetic code redundancies are considered inconsequential to protein structure. This study uncovers a dependence between local amino acid conformation in folded proteins and the identity of the codon from which that amino acid was translated.
- Aviv A. Rosenberg
- , Ailie Marx
- & Alex M. Bronstein
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Article
| Open AccessStructural rearrangements allow nucleic acid discrimination by type I-D Cascade
I-D CRISPR-Cascade can target both single-stranded and double-stranded nucleic acids. Here, Schwartz et. al determine these structures and reveal large-scale rearrangements that allow for target discrimination and destruction.
- Evan A. Schwartz
- , Tess M. McBride
- & David W. Taylor
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Article
| Open AccessRibosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM
The expansion of GGGGCC repeats in the C9ORF72 gene results in the production of disease causing abnormal proteins with polymeric glycine-arginine (poly-GR) and polymeric proline-arginine (poly-PR). Here the authors demonstrate a structural mechanism of how poly-GR and poly-PR inhibit translation and how they might also perturb ribosome assembly.
- Anna B. Loveland
- , Egor Svidritskiy
- & Andrei A. Korostelev
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Article
| Open AccessStructural mechanism of TRPV3 channel inhibition by the anesthetic dyclonine
TRPV3 mediates cutaneous sensations such as itch and pain. Here authors present the cryo-EM structure of TRPV3 bound with local anesthetic which binds the channel in membrane portals that connect the membrane environment to the channel pore.
- Arthur Neuberger
- , Kirill D. Nadezhdin
- & Alexander I. Sobolevsky
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Article
| Open AccessInhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC
TMEM16A, a calcium-activated chloride channel involved in multiple cellular processes, is implicated in various diseases, but its pharmacology remains poorly understood. Here, the authors combine cryo-EM and electrophysiology to elucidate the mechanism of TMEM16A inhibition by the pore blocker 1PBC.
- Andy K. M. Lam
- , Sonja Rutz
- & Raimund Dutzler
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Article
| Open AccessStructural insights into the mechanism of pancreatic KATP channel regulation by nucleotides
KATP channels are energy sensors. Here, authors report the Cryo-EM structures of pancreatic KATP in both the closed state and the pre-open state. These structures illuminate the mechanism of KATP channel regulation by the intracellular nucleotides.
- Mengmeng Wang
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessCryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy
Using cryo-EM, Chung et al. investigate conformational states of mammalian respiratory complex I to reveal an ubiquinone-10 molecule occupying the full length of the Q-binding channel. Molecular dynamics simulations suggest how the charge states of key residues influence the substrate binding pose.
- Injae Chung
- , John J. Wright
- & Judy Hirst
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Article
| Open AccessOrigins of glycan selectivity in streptococcal Siglec-like adhesins suggest mechanisms of receptor adaptation
Streptococcal siglec-like binding regions (SLBRs) selectively bind cell surface glycans, but the basis for this selectivity is not understood. Here, the authors identify selectivity-modulating SLBR regions and study how changes in SLBR glycan selectivity affect interactions with human glycoprotein receptors.
- Barbara A. Bensing
- , Haley E. Stubbs
- & T. M. Iverson
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Article
| Open AccessStructural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide
Loop diuretics including bumetanide inhibit Na+-K+-Cl−-cotransporters (NKCCs) and are used for the treatment of edema and hypertension. Here, Zhao et. al. report structures of NKCC1 with bumetanide bound, revealing its mechanism of action that would facilitate design of novel diuretics.
- Yongxiang Zhao
- , Kasturi Roy
- & Erhu Cao
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Article
| Open AccessPhase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas
Oncoprotein SS18-SSX is a hallmark of synovial sarcoma. Here the authors report phase separation of SS18-SSX and the binding of SS18-SSX to chromatin remodeling complex are important for the transformation activity of the oncoprotein SS18-SSX.
- Yanli Cheng
- , Zhongtian Shen
- & Jiafu Long
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Article
| Open AccessN-type fast inactivation of a eukaryotic voltage-gated sodium channel
Voltage-gated sodium channels mediate electrical signaling. Here, authors report the cryo-EM structure of NaVEh from the marine plant Emiliania huxleyi, revealing an unexpected mechanism of N-type fast inactivation.
- Jiangtao Zhang
- , Yiqiang Shi
- & Daohua Jiang
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Article
| Open AccessA nucleotide-sensing oligomerization mechanism that controls NrdR-dependent transcription of ribonucleotide reductases
Ribonucleotide reductase (RNR) is an essential enzyme that catalyzes the synthesis of DNA building blocks. Here, the authors present the cryo-EM structure and mechanism of action of NrdR, the RNR-specific repressor, that controls transcription of RNR genes in bacteria.
- Inna Rozman Grinberg
- , Markel Martínez-Carranza
- & Pål Stenmark
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Article
| Open AccessCa2+-mediated higher-order assembly of heterodimers in amino acid transport system b0,+ biogenesis and cystinuria
Cystinuria is caused by mutations in heterodimeric amino acid transporter known as system b0,+. Here, authors discover that Ca2+ stabilizes the interface between two system b0,+ regulatory subunits rBAT, leading to super-dimerization of the b0,+AT–rBAT heterodimer, facilitating system b0,+ maturation.
- Yongchan Lee
- , Pattama Wiriyasermkul
- & Shushi Nagamori
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Article
| Open AccessStructural identification of vasodilator binding sites on the SUR2 subunit
SUR2-containing KATP channels are drug targets for certain vasodilators. Here, the authors determine high-resolution cryo-EM structures of SUR2 in complex with two vasodilators, P1075 and levcromakalim, uncovering the mechanisms of these drugs.
- Dian Ding
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessActive conformation of the p97-p47 unfoldase complex
The p97 unfoldase is an essential and abundant enzyme that segregates its substrates from macromolecular complexes and organelle membranes. Here, authors determined the structure of human p97 in the act of unfolding an authentic substrate.
- Yang Xu
- , Han Han
- & Peter S. Shen
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Article
| Open AccessSignal transduction in light-oxygen-voltage receptors lacking the active-site glutamine
Light-oxygen-voltage (LOV) photoreceptors perceive blue light to elicit spatio-temporally defined cellular responses, and their signalling process has been extensively characterized. Here the authors report that the light signal is still transduced in the absence of a conserved Gln residue, thought to be key.
- Julia Dietler
- , Renate Gelfert
- & Andreas Möglich
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Article
| Open AccessStructure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex
NALCN channel mediates sodium leak currents and is essential for neuronal activity. Here authors uncover the mechanism of how UNC79 and UNC80 interact and promote the function of NALCN channel.
- Yunlu Kang
- & Lei Chen
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Article
| Open AccessMolecular insights into biogenesis of glycosylphosphatidylinositol anchor proteins
GPI-T catalyzes the committed step in GPI anchor protein biogenesis. Here, Xu et al. report the cryo-EM structure of the human GPI-T, revealing critical elements within an elongated, shared active site which is topologically arranged for substrate specificity.
- Yidan Xu
- , Guowen Jia
- & Dianfan Li
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Article
| Open AccessStructural basis of ion – substrate coupling in the Na+-dependent dicarboxylate transporter VcINDY
DASS carboxylate transporters linked to metabolic diseases couple the Na+ gradient to nutrient uptake. Here, the authors unravel the structural basis by which Na+ binding coordinates substrate interactions, revealing a distinct coupling mechanism.
- David B. Sauer
- , Jennifer J. Marden
- & Da-Neng Wang
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Article
| Open AccessMolecular basis for inhibiting human glucose transporters by exofacial inhibitors
Human glucose transporters (GLUTs), particularly GLUT1 and GLUT3, are potential anticancer therapy targets. Here, Nan Wang et al. use an engineered GLUT 3 variant to identify an exofacial GLUT3 inhibitor, SA47, and elucidate the drug’s inhibitory mechanism.
- Nan Wang
- , Shuo Zhang
- & Nieng Yan
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Article
| Open AccessSubstrate recognition and cryo-EM structure of the ribosome-bound TAC toxin of Mycobacterium tuberculosis
Toxin-antitoxin systems are widespread in bacteria. Here the authors present structures of M. tuberculosis HigBTAC alone and bound to the ribosome in the presence of native cspA mRNA, shedding light on its mechanism of translation inhibition.
- Moise Mansour
- , Emmanuel Giudice
- & Pierre Genevaux
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Article
| Open AccessTMEM16 scramblases thin the membrane to enable lipid scrambling
Lipid scrambling is required for many cellular processes but the lipid-protein interactions that occur during transport are unknown. Using cryoEM and biochemical assays the authors show that membrane thinning is critical for lipid flipping.
- Maria E. Falzone
- , Zhang Feng
- & Alessio Accardi
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Article
| Open AccessThe pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites
G-protein-coupled receptors bind endogenous ligands at sites that are frequently highly conserved. Here, authors computationally describe alternative allosteric pockets, several of which have not been targeted by synthetic ligands before.
- Janik B. Hedderich
- , Margherita Persechino
- & Peter Kolb
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Article
| Open AccessIdentification of oleoylethanolamide as an endogenous ligand for HIF-3α
Whether hypoxia-inducible factors (HIFs) can be directly regulated by endogenous small molecules is a long-standing question. Here authors identified the metabolite oleoylethanolamide as a HIF-3α ligand and further revealed its mechanism of action.
- Xiaotong Diao
- , Fei Ye
- & Dalei Wu
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Article
| Open AccessMolecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors
Acquired drug resistance is common during chemotherapy. Here, the authors describe the structural basis and molecular mechanism by which allosteric and clinically approved, ATP-competitive inhibitors of EGFR synergize to overcome resistance in lung cancer.
- Tyler S. Beyett
- , Ciric To
- & Michael J. Eck
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Article
| Open AccessCryo-EM structures of thylakoid-located voltage-dependent chloride channel VCCN1
VCCN1 is a plant homolog of bestrophin channels and tunes photoreaction as a voltage-gated anion channel at thylakoids. Here, authors report the cryo-EM structures and functional features of apple VCCN1, with insights into its activation mechanism.
- Tatsuya Hagino
- , Takafumi Kato
- & Osamu Nureki
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Article
| Open AccessStructure of the Arabidopsis guard cell anion channel SLAC1 suggests activation mechanism by phosphorylation
The anion channel SLAC1 controls stomatal closure upon phosphoactivation. Here via structural analysis and electrophysiology, the authors propose an inhibition-release model where phosphorylation causes dissociation of a cytosolic plug from the SLAC1 transmembrane domains to induce conformational change in the pore-forming helices.
- Yawen Li
- , Yinan Ding
- & Linfeng Sun
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Article
| Open AccessEPicker is an exemplar-based continual learning approach for knowledge accumulation in cryoEM particle picking
Many existing deep learning algorithms for particle picking are not predictable on unseen datasets. Here the authors report an exemplar-based continual learning approach, EPicker, enabling accumulation of new knowledge of cryoEM particle picking without catastrophic forgetting of old knowledge.
- Xinyu Zhang
- , Tianfang Zhao
- & Xueming Li
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Article
| Open AccessCofilactin filaments regulate filopodial structure and dynamics in neuronal growth cones
In this manuscript the authors show that Filopodia switch between bundles of fascin-crosslinked actin and cofilin-decorated filaments, which exclude fascin binding due to altered structure and packing, as well as affect filopodial searching dynamics.
- Ryan K. Hylton
- , Jessica E. Heebner
- & Matthew T. Swulius
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Article
| Open AccessCrystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10
Mutations in BMPR2 is the major genetic cause for pulmonary arterial hypertension (PAH). Here by solving crystal structures of BMPRII in binary and ternary receptor complexes with BMP10, the authors report the molecular recognition between BMPRII and BMP10, and its implication in PAH.
- Jingxu Guo
- , Bin Liu
- & Wei Li
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Article
| Open AccessStructural basis for the synthesis of the core 1 structure by C1GalT1
The glycosyltransferase C1GalT1 directs a key step in protein O-glycosylation important for the expression of the cancer-associated Tn and T antigens. Here, the authors provide molecular insights into the function of C1GalT1 by solving the crystal structure of the Drosophila enzyme-substrate complex.
- Andrés Manuel González-Ramírez
- , Ana Sofia Grosso
- & Ramon Hurtado-Guerrero
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Article
| Open AccessMultivalent interactions essential for lentiviral integrase function
The authors determined high-resolution cryo-EM structures of the lentiviral intasome — the nucleoprotein complex that inserts viral DNA into a host chromosome — and show that the architecture comprising 16 integrase subunits is critical for its function.
- Allison Ballandras-Colas
- , Vidya Chivukula
- & Peter Cherepanov
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Article
| Open AccessStructural basis for the inhibition of IAPP fibril formation by the co-chaperonin prefoldin
Integrated kinetic and structural investigations reveal that the ubiquitous co-chaperonin prefoldin interacts with its coiled-coil helices on the islet amyloid polypeptide fibril surface and fibril ends to inhibit fibril elongation and secondary nucleation.
- Ricarda Törner
- , Tatsiana Kupreichyk
- & Jerome Boisbouvier
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Article
| Open AccessUnique binding pattern for a lineage of human antibodies with broad reactivity against influenza A virus
While most broadly neutralizing antibodies (bnAb) against Influenza virus target conserved conformational epitopes of the glycoprotein hemagglutinin (HA), Sun et al. characterize a lineage of bnAbs that neutralize group 1 and 2 strains. Structural characterization shows that antibody 28-12 binds a continuous epitope within H3 (group 2) but requires a conformational epitope for H1 (group 1) binding. Comparison of germline-reverted Ab and intermediate mutants provides evidence for an evolutionary adaptation from group 2 to group 1 strain.
- Xiaoyu Sun
- , Caixuan Liu
- & Bing Sun
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Article
| Open AccessActivation and allosteric regulation of the orphan GPR88-Gi1 signaling complex
GPR88 is an orphan GPCR and regulates diverse brain functions. Here, the authors report two structures of the human GPR88-Gi complex, showing an allosteric ligand directly involved in the interaction interface between the receptor and G-protein, and a density which may represent an endogenous ligand of GPR88.
- Geng Chen
- , Jun Xu
- & Yang Du
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Article
| Open AccessFormation of thyroid hormone revealed by a cryo-EM structure of native bovine thyroglobulin
Thyroid hormones are formed within the precursor Thyroglobulin by a poorly understood process. Here Marechal et al. report a cryo-EM structure of native bovine Thyroglobulin with nascent thyroid hormone formed at a predicted hormone synthesis site.
- Nils Marechal
- , Banyuhay P. Serrano
- & Charles J. Weitz
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Article
| Open AccessIn crystallo observation of three metal ion promoted DNA polymerase misincorporation
By observing DNA polymerase misincorporation with time-resolved crystallography, the authors visualize three-metal ion dependent polymerase catalysis and identify A-site metal-mediated primer alignment as a key step in nucleotide discrimination.
- Caleb Chang
- , Christie Lee Luo
- & Yang Gao
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Article
| Open AccessMechanism of integrin activation by talin and its cooperation with kindlin
The authors report here that talin and kindlin, the two key integrin binders and activators, are bridged by paxillin to induce microclustering of integrins to potently bind to multivalent extracellular ligand and trigger rapid cell attachment.
- Fan Lu
- , Liang Zhu
- & Jun Qin
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Article
| Open AccessMolecular basis of antibiotic self-resistance in a bee larvae pathogen
The authors show that the N-acetyltransferase PamZ acts as a self-resistance factor disabling the antibacterial paenilamicin that is produced by the honey bee larvae pathogen Paenibacillus larvae.
- Tam Dang
- , Bernhard Loll
- & Roderich D. Süssmuth
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Article
| Open AccessStructural insights into TRPV2 activation by small molecules
A non-selective calcium channel transient receptor potential vanilloid 2 (TRPV2) is a potential drug target. Here, the authors employ cryo-electron microscopy, in silico docking, and electrophysiology to identify a binding site for an activator 2-aminoethoxydiphenyl borate (2-APB) in this channel.
- Ruth A. Pumroy
- , Anna D. Protopopova
- & Vera Y. Moiseenkova-Bell
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Article
| Open AccessCrystal structures and insights into precursor tRNA 5’-end processing by prokaryotic minimal protein-only RNase P
HARP are member of protein-only RNase P, which catalyzes pre-tRNA 5’-end processing and maturation. Here, the authors present crystal structure and provide mechanistic insights into pre-tRNA binding and cleavage by HARP proteins.
- Yangyang Li
- , Shichen Su
- & Jianhua Gan
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Article
| Open AccessThree-dimensional structure determination of protein complexes using matrix-landing mass spectrometry
Mass spectrometry (MS) is a powerful tool for the structural characterization of protein complexes. Here the authors offer a path for direct integration of MS and electron microscopy with a MS approach that enables grid deposition and structural preservation of gaseous protein complex ions.
- Michael S. Westphall
- , Kenneth W. Lee
- & Joshua J. Coon