Featured
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Article
| Open AccessThe cytoplasmic synthesis and coupled membrane translocation of eukaryotic polyphosphate by signal-activated VTC complex
The VTC complex generate eukaryotic polyphosphate (polyP). Authors here reveal how the signal-activated VTC synthesize cytosolic polyP and transport polyP across vacuolar membrane into the lumen, by using cryo-EM, in-cell NMR, and smFRET analyses.
- Zeyuan Guan
- , Juan Chen
- & Zhu Liu
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Article
| Open AccessMORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain
Human acetyltransferases MOZ and MORF mediate development programs and are dysregulated in diseases. Here the authors identified two winged helix (WH) domains in MORF/MOZ and characterized their DNA binding functions, including targeting of CpG by WH1.
- Dustin C. Becht
- , Brianna J. Klein
- & Tatiana G. Kutateladze
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Article
| Open AccessIsoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder
Adhesion GPCRs have numerous functions, ligands and isoforms. Here, Kordon et al. report synthetic antibodies that both modulate aGPCR signaling in an isoform-specific manner, and break receptor interactions in a ligand-specific manner
- Szymon P. Kordon
- , Przemysław Dutka
- & Demet Araç
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Article
| Open AccessDirect Cryo-ET observation of platelet deformation induced by SARS-CoV-2 spike protein
SARS-CoV-2 infection can cause coagulopathic events. Kuhn et al. show by cryo-ET how the Spike protein impacts platelet morphology by binding to the platelet surface, leading to micro-activation; and investigate integrin as possible point of contact.
- Christopher Cyrus Kuhn
- , Nirakar Basnet
- & Naoko Mizuno
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Article
| Open AccessThe AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system
Tau aggregates are associated with several neurodegenerative disorders. In this work, I. Saha and colleagues show that valosin-containing protein (VCP) recruited to Tau fibrils disaggregates them. However, this process comes at a cost: it generates seeding-active Tau species as byproduct.
- Itika Saha
- , Patricia Yuste-Checa
- & Mark S. Hipp
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Article
| Open AccessSingle-exonuclease nanocircuits reveal the RNA degradation dynamics of PNPase and demonstrate potential for RNA sequencing
Observing the natural process of RNA degradation in real-time is a significant challenge. Here, the authors develop and use single-exonuclease nanocircuits to reveal the single-base degradation behaviour of PNPase, and demonstrate proof-of-principle RNA sequencing using this approach.
- Zhiheng Yang
- , Wenzhe Liu
- & Xuefeng Guo
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Article
| Open AccessMechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor
Follicle stimulating hormone (FSH) is a glycoprotein hormone the functions of which are mediated by a G protein-coupled receptor, FSHR. Here, Duan et al. report cryo-EM structures of FSHR in active and inactive states, suggesting the molecular basis of FSH and small allosteric agonist-mediated FSHR activation.
- Jia Duan
- , Peiyu Xu
- & H. Eric Xu
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Article
| Open AccessLigand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)
Relaxin family peptide receptor 4 (RXFP4) regulates pleiotropic biological processes. Here, authors report cryo-EM structures revealing the ligand-binding modes and key determinants of peptidomimetic agonism and subtype selectivity
- Yan Chen
- , Qingtong Zhou
- & Ming-Wei Wang
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Article
| Open AccessStructural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor
Here, using cryo-electron microscopy and solution NMR, the authors reveal the structural and dynamic mechanisms underlying the signaling versatility of a muscarinic receptor regulated by orthosteric and allosteric ligands.
- Jun Xu
- , Qinggong Wang
- & Brian K. Kobilka
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Article
| Open AccessCryo-EM reveals the molecular basis of laminin polymerization and LN-lamininopathies
In this work the authors report the cryo-EM structure of the laminin polymer node and reveal the molecular basis of calcium-dependent formation of laminin lattice. The work provides insights into laminin polymerization defects manifesting in human disease.
- Arkadiusz W. Kulczyk
- , Karen K. McKee
- & Peter D. Yurchenco
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Article
| Open AccessRevealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling
Visualizing endogenous GPCRs is challenging. Here the authors generate mice with an enzyme self-label genome-edited into the endogenous glucagon-like peptide-1 receptor locus, design fluorescent dyes for specific labelling in complex tissue, and reveal tissue-level organisation and dynamics of an endogenous class B GPCR.
- Julia Ast
- , Daniela Nasteska
- & David J. Hodson
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Article
| Open AccessEnhancement of a prime editing system via optimal recruitment of the pioneer transcription factor P65
Prime editing represents a great advance to the genome editing field but is currently limited by the editing efficiency. Here the authors look to improve the efficiency by recruiting target proteins and show that the transcription factor P65 could enhance the desired editing outcomes at different gene loci.
- Ronghao Chen
- , Yu Cao
- & Xueli Zhang
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Article
| Open AccessCryo-EM structures of orphan GPR21 signaling complexes
In this work, the authors report Cryo-EM structures of the signaling complexes of human GPR21, an orphan GPCR and a potential metabolic disease target, and reveal unique receptor activation conformation when bound to downstream signaling proteins in the absence of any ligand.
- Xi Lin
- , Bo Chen
- & Fei Xu
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Article
| Open AccessDecoding of the ubiquitin code for clearance of colliding ribosomes by the RQT complex
The colliding ribosomes are ubiquitinated by the sensor protein Hel2, leading to noncanonical subunit dissociation by the ribosome associated quality control trigger (RQT) complex. Here the authors reveal the decoding mechanism of the ribosome ubiquitin code by the RQT complex.
- Yoshitaka Matsuo
- , Takayuki Uchihashi
- & Toshifumi Inada
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Article
| Open AccessThermodynamic architecture and conformational plasticity of GPCRs
GPCRs are integral membrane proteins that serve as attractive drug targets. Here, authors delineate the conformational landscapes of 45 GPCRs using a statistical model, highlighting their malleable native ensembles and providing functional insights.
- Sathvik Anantakrishnan
- & Athi N. Naganathan
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Article
| Open AccessStructure of the Sec14 domain of Kalirin reveals a distinct class of lipid-binding module in RhoGEFs
A subset of Sec14 domain proteins use their gated hydrophobic pocket to bind and transport lipids. Here the authors provide structural and biochemical data revealing how the Sec14-fold of a Rho-GEF forms a surface groove that interacts with lysolipids.
- Yunfeng Li
- , Yulia Pustovalova
- & Bing Hao
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Article
| Open AccessThe mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase
The mitochondrial ATP synthase produces the bulk of cellular ATP. Here, the authors report a function of the mitochondrial Hsp70 in the formation of the catalytical head and in its assembly with the peripheral stalk to form the mature ATP synthase.
- Jiyao Song
- , Liesa Steidle
- & Thomas Becker
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Article
| Open AccessLigand recognition and activation of neuromedin U receptor 2
Neuromedin U receptor 2 is an emerging attractive target for treating obesity. Here, a Cryo-EM structure of NmU-25–NMU2–Gi1 provides the structural basis for the designation of highly selective drugs.
- Wenli Zhao
- , Wenru Zhang
- & Qiang Zhao
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Article
| Open AccessSimultaneous profiling of histone modifications and DNA methylation via nanopore sequencing
The interplay between histone modifications and DNA methylation plays a crucial role in establishing and maintaining the epigenomic landscape. Here, the authors develop a nanopore sequencing based method for mapping histone modifications and DNA methylation from native, long, single DNA molecules.
- Xue Yue
- , Zhiyuan Xie
- & Yimeng Yin
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Article
| Open AccessThousands of human non-AUG extended proteoforms lack evidence of evolutionary selection among mammals
Analysis of a large number of Ribo-seq datasets and genomic alignments led to detection of novel non-AUG proteoforms. Unexpectedly the number of non-AUG proteoforms identified with Ribo-seq greatly exceeds those with strong phylogenetic support.
- Alla D. Fedorova
- , Stephen J. Kiniry
- & Pavel V. Baranov
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Article
| Open AccessA conformation-specific nanobody targeting the nicotinamide mononucleotide-activated state of SARM1
SARM1 is a key player in axon degeneration. Here, the authors generate a nanobody, which specifically recognizes the NMN-bound state of SARM1 and helps resolve the SARM1 structure in an intermediate state of activation.
- Yun Nan Hou
- , Yang Cai
- & Yong Juan Zhao
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Article
| Open AccessStructure of a RecT/Redβ family recombinase in complex with a duplex intermediate of DNA annealing
Specific ssDNA binding proteins promote the annealing of complementary strands. Here the authors reveal an intermediate of annealing in which a duplex DNA is bound in an unusual conformation that is highly extended and unwound for the ssDNA binding protein Redβ from bacteriophage λ.
- Brian J. Caldwell
- , Andrew S. Norris
- & Charles E. Bell
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Article
| Open AccessActivating alternative transport modes in a multidrug resistance efflux pump to confer chemical susceptibility
Antibiotic resistance through multidrug efflux is a major hurdle in antibiotic development. Here, authors experimentally demonstrate that EmrE, a small multidrug resistance efflux pump from E. coli, can confer resistance or susceptibility depending on the small molecule substrate.
- Peyton J. Spreacker
- , Nathan E. Thomas
- & Katherine A. Henzler-Wildman
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Article
| Open AccessIdentifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases
Antimicrobial resistance to currently available antibiotics requires innovation of antibiotics. Here, the authors identify a critical inhibitory site in an energy-producing enzyme, which can lead to rational design of antibiotics.
- Yuya Nishida
- , Sachiko Yanagisawa
- & Yasunori Shintani
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Article
| Open AccessDiscovery and structure of a widespread bacterial ABC transporter specific for ergothioneine
The extent to which human bacterial pathogens broadly utilize ergothioneine as an antioxidant is unknown. Here, authors describe the discovery of a specific transporter for ergothioneine in a respiratory pathogen that is highly conserved among Firmicutes.
- Yifan Zhang
- , Giovanni Gonzalez-Gutierrez
- & David P. Giedroc
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Article
| Open AccessBackbone amides are determinants of Cl− selectivity in CLC ion channels
CLC-type channels selectively transport Cl− across biological membranes, but it is unclear how discrimination between anions is maintained. Here, authors use a combination of non-natural amino acid substitutions, electrophysiology, and molecular dynamics simulations to determine Cl− specificity within this family of ion channels.
- Lilia Leisle
- , Kin Lam
- & Alessio Accardi
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Article
| Open AccessThe role of auxiliary domains in modulating CHD4 activity suggests mechanistic commonality between enzyme families
CHD4 is an essential chromatin remodelling enzyme in complex organisms. Here the authors demonstrate that CHD4 activity is regulated both positively and negatively by distinct auxiliary domains, revealing parallels with other chromatin remodellers.
- Yichen Zhong
- , Hakimeh Moghaddas Sani
- & Joel P. Mackay
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Article
| Open AccessStructural basis of sequence-specific RNA recognition by the antiviral factor APOBEC3G
Interaction between APOBEC3G and RNA is critical for its antiviral function. Here, the authors report four co-crystal structures of rhesus macaque APOBEC3G and RNA, demonstrating unpaired AA and GA dinucleotide motifs are preferentially recognized.
- Hanjing Yang
- , Kyumin Kim
- & Xiaojiang S. Chen
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Article
| Open AccessDynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity
G protein coupled receptors (GPCRs) can couple to different Gα protein subfamilies either selectively or promiscuously. Here, the authors use computational approach to show that selectivity determinants are at the periphery of the GPCR—G protein interface and that promiscuous GPCRs more frequently sample the common rather than selective contacts.
- Manbir Sandhu
- , Aaron Cho
- & Nagarajan Vaidehi
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Article
| Open AccessNascent peptide-induced translation discontinuation in eukaryotes impacts biased amino acid usage in proteomes
Here the authors find that nascent chains enriched in acidic amino acids destabilize the translating ribosome, eventually leading to stochastic premature termination in eukaryotes as in bacteria. Such risk of premature termination influences the amino acid distribution in the proteomes.
- Yosuke Ito
- , Yuhei Chadani
- & Hideki Taguchi
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Article
| Open AccessA unified computational framework for single-cell data integration with optimal transport
Integrating heterogeneous single-cell multi-omics as well as spatially resolved transcriptomic data remains a major challenge. Here the authors report a unified single-cell data integration framework using an unbalanced optimal transport-based deep network.
- Kai Cao
- , Qiyu Gong
- & Lin Wan
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Article
| Open AccessStructures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments
Voltage-gated Ca2+ channel subtype Cav2.3 represents a potential drug target for neurological diseases. Here, authors report cryo-EM structures of Cav2.3 and its mutant to reveal the crosstalk of intracellular segments, which may facilitate future drug discovery.
- Xia Yao
- , Yan Wang
- & Nieng Yan
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Article
| Open AccessCryoEM structure and assembly mechanism of a bacterial virus genome gatekeeper
Numerous viruses use a portal system for dsDNA entry and exit from their capsid. Here the authors report the atomic structure of phage SPP1 portal DNA gatekeeper and its mechanism of assembly. They also identify evolution breakpoints between different tailed bacteriophages morphotypes and herpesviruses.
- Igor Orlov
- , Stéphane Roche
- & Elena V. Orlova
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Article
| Open AccessStructural basis for lipid and copper regulation of the ABC transporter MsbA
The bacterial ABC transporter MsbA is essential for lipopolysaccharide biogenesis. Here, the authors apply native mass spectrometry, X-ray crystallography, cryo-EM and biochemical approaches to characterize the structural basis and functional roles of MsbA binding to copper and specific lipids.
- Jixing Lyu
- , Chang Liu
- & Arthur Laganowsky
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Article
| Open AccessGating and ion selectivity of Channelrhodopsins are critical for photo-activated orientation of Chlamydomonas as shown by in vivo point mutation
Channelrhodopsin photoreceptors are responsible for phototaxis in C. reinhardtii. Here, authors introduce point mutations in the channel which modify photocycle kinetics and ion selectivity, resulting in a deeper understanding of phototaxis in low light conditions.
- Olga Baidukova
- , Johannes Oppermann
- & Peter Hegemann
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Article
| Open AccessConstruction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor
Chemical libraries with skeleton diversity are important for drug discovery. Here, the authors establish a synthetic methodology-based compound library (SMBL), and apply it to identify a small-molecule inhibitor to interrupt a challenging target: the protein–protein interaction (PPI) of GIT1/β-Pix.
- Jing Gu
- , Rui-Kun Peng
- & Qin Ouyang
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Article
| Open AccessUptake mechanism of iron-phytosiderophore from the soil based on the structure of yellow stripe transporter
Iron is an essential mineral in plant physiology. YS1 transporter imports iron–phytosiderophore complex (Fe(III)–DMA) from the soil. Here, the authors describe the cryo-EM structures of barley YS1 in complex with substrate, and a synthetic substrate analog.
- Atsushi Yamagata
- , Yoshiko Murata
- & Mikako Shirouzu
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Article
| Open AccessSmc5/6’s multifaceted DNA binding capacities stabilize branched DNA structures
Using single-molecule visualization and manipulation, Chang et al. show that the eukaryotic Smc5/6 complex preferentially binds to and stabilizes ssDNA-dsDNA junctions, which could serve as the molecular basis for its diverse roles in genome maintenance.
- Jeremy T-H. Chang
- , Shibai Li
- & Shixin Liu
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Article
| Open AccessPhase separation modulates the assembly and dynamics of a polarity-related scaffold-signaling hub
The polarization of distinct scaffold-signaling hubs at opposite cell poles constitutes the basis of asymmetric cell division. Here, the authors show that phase separation serves as a general mechanism to regulate the assembly and dynamics of a new-pole scaffold-signaling hub.
- Wei Tan
- , Sihua Cheng
- & Wei Zhao
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Article
| Open AccessStructural basis of synthetic agonist activation of the nuclear receptor REV-ERB
The nuclear receptor REV-ERBα is a receptor for heme and plays a role in a range of physiological processes. Here, the authors provide the first structure of REV-ERB bound to a synthetic nonporphyrin ligand defining key mechanistic differences to how heme binds.
- Meghan H. Murray
- , Aurore Cecile Valfort
- & Thomas P. Burris
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Article
| Open AccessPPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation
Mutations in PPARγ lead to lipodystrophy, but the mechanisms by which the mutations affect the activity in chromatin is unknown. Here, Madsen, Broekema et al. showed that mutations affecting two intermolecular interactions compromise chromatin remodeling.
- Maria Stahl Madsen
- , Marjoleine F. Broekema
- & Eric Kalkhoven
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Article
| Open AccessPhosphorylation disrupts long-distance electron transport in cytochrome c
Electron transfer between mitochondrial cytochrome c and subunit of cytochrome bc1 can proceed at long distance. Here the authors investigate further the mechanism and show phosphorylation regulation of the interactions between the protein partners in the electron transport chain.
- Alexandre M. J. Gomila
- , Gonzalo Pérez-Mejías
- & Anna Lagunas
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Article
| Open AccessActivation and signaling mechanism revealed by GPR119-Gs complex structures
Agonists selectively targeting GPR119 hold promise for treating metabolic disorders. Here, authors reveal that GPR119 adopts a non-canonical consensus structural scaffold with an extended ligand-binding pocket for chemically different agonists.
- Yuxia Qian
- , Jiening Wang
- & Anna Qiao
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Article
| Open AccessCryo-EM structure of ex vivo fibrils associated with extreme AA amyloidosis prevalence in a cat shelter
Here, the authors report the cryoEM structure of AA amyloid from a cat shelter with extreme disease prevalence and reveal the feline-specific sequence insert in the fibril core. The sequence is 99% identical to AA amyloid from cheetah with reported prion-like transmission in zoos.
- Tim Schulte
- , Antonio Chaves-Sanjuan
- & Stefano Ricagno
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Article
| Open AccessMechanochemical tuning of a kinesin motor essential for malaria parasite transmission
Plasmodium kinesin-8B is essential for male gamete formation and its absence blocks parasite transmission. Using cryo-EM and TIRF, the authors report how kinesin-8B motor domains are tuned to support microtubule motility and depolymerase activity.
- Tianyang Liu
- , Fiona Shilliday
- & Carolyn A. Moores
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Article
| Open AccessF-actin architecture determines constraints on myosin thick filament motion
While the impact of F-actin architecture on stress transmission is well studied, the role of architecture on stress generation remains unclear. Here authors use in vitro model and show that distinct organizations constrain myosin motion.
- Camelia G. Muresan
- , Zachary Gao Sun
- & Michael P. Murrell
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Article
| Open AccessUnderstanding VPAC receptor family peptide binding and selectivity
Previously, peptide selectivity in the VPAC receptor family of GPCRs was poorly understood. Here, authors combine cryo-EM and MD data to understand binding and selectivity of VPAC1R and PAC1R peptide agonists that can guide future drug development.
- Sarah J. Piper
- , Giuseppe Deganutti
- & Denise Wootten
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Article
| Open AccessStructural basis for mechanotransduction in a potassium-dependent mechanosensitive ion channel
Mechanosensitive ion channels mediate biological force sensation, but the underlying mechanism remains poorly understood. Here, authors present the structural basis of mechanotransduction in an ion channel revealed by cryo-electron microscopy.
- Jonathan Mount
- , Grigory Maksaev
- & Peng Yuan
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Article
| Open AccessSite-selective photocatalytic functionalization of peptides and proteins at selenocysteine
The modification of peptides and proteins for application in drug discovery and chemical biology is currently a rapidly growing field of research. Here, the authors report a photocatalytic diselenide contraction method for the dimerization and site-specific functionalisation of peptides and protein.
- Luke J. Dowman
- , Sameer S. Kulkarni
- & Richard J. Payne
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