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| Open AccessMolecular mechanism of phosphopeptide neoantigen immunogenicity
Phosphorylated peptide antigens are present on cancer cells, but their role in cancer immunity is unknown. Here, the authors describe a molecular mechanism, by which a tumor-specific phosphopeptide found in acute myeloid leukemia is recognized by the human immune T cells.
- Yury Patskovsky
- , Aswin Natarajan
- & Michelle Krogsgaard
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Article
| Open AccessMechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005
Using solution-state NMR spectroscopy, the authors followed the individual steps involved in protein misfolding from the native to the amyloid fibril state for the antibody light chain (AL) amyloidosis related protein FOR005.
- Tejaswini Pradhan
- , Riddhiman Sarkar
- & Bernd Reif
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Article
| Open AccessStructural basis of protein condensation on microtubules underlying branching microtubule nucleation
TPX2 is a key factor stimulating branching microtubule (MT) nucleation. TPX2 forms condensates on MTs critical for branching. In this work, the authors report the atomic-level structure of TPX2 C-terminal minimal active domain on MT lattice and its binding interface, determined by magic-angle-spinning NMR.
- Changmiao Guo
- , Raymundo Alfaro-Aco
- & Tatyana Polenova
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Article
| Open AccessThe preference signature of the SARS-CoV-2 Nucleocapsid NTD for its 5’-genomic RNA elements
SARS-CoV-2 genome turnover is mediated by its N protein, but precise parameters driving the necessary RNA specificity have remained enigmatic. Here, Korn et al. reveal N’s N-terminal domain to distinguish regulatory viral RNA motifs with a preference for transiently folded elements of functional impact.
- Sophie Marianne Korn
- , Karthikeyan Dhamotharan
- & Andreas Schlundt
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Article
| Open AccessStabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314
The authors highlight the importance of kinetics in GPCR activation. Using solution NMR, they show that the transducer βarrestin1 and the β-arrestin1biased ligand ML314 kinetically tune the conformational ensemble of the neurotensin receptor 1.
- Fabian Bumbak
- , James B. Bower
- & Joshua J. Ziarek
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Article
| Open AccessThe UBX domain in UBXD1 organizes ubiquitin binding at the C-terminus of the VCP/p97 AAA-ATPase
The function of VCP/p97 AAA-ATPase cofactor UBXD1 and its UBX domain has been elusive. Here the authors show that the extended UBXD1 UBX domain is located at the p97 pore exit where it binds ubiquitin, suggesting that UBXD1 receives unfolded substrates and hands them off for down-stream processing.
- Mike Blueggel
- , Alexander Kroening
- & Christine Beuck
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Article
| Open AccessEarly events in amyloid-β self-assembly probed by time-resolved solid state NMR and light scattering
Here the authors report time-resolved experiments showing that amyloid-β peptide molecules become partially structured even before they adhere to one another, within one millisecond. Peptide conformations change only slightly as assemblies grow in size for many minutes.
- Jaekyun Jeon
- , Wai-Ming Yau
- & Robert Tycko
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Article
| Open AccessInositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction
Pipercevic et al resolve how inositol molecules activate the VTC protein complex. The VTC complex stores phosphate in yeast and is controlled by SPX domains. The inositol molecules break an interaction between SPX domains to activate the complex.
- Joka Pipercevic
- , Bastian Kohl
- & Sebastian Hiller
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Article
| Open AccessDual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin
Understanding mechanisms of PLpro substrate selectivity offers new ways to decouple substrate activities and will inform new therapeutic strategies. Here, the authors use multi-disciplinary approaches to uncover how PLpro from SARS-CoV-2 can discriminate between different substrates.
- Pawel M. Wydorski
- , Jerzy Osipiuk
- & Lukasz A. Joachimiak
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Article
| Open AccessSolvent-derived defects suppress adsorption in MOF-74
Defects in metal-organic frameworks impact their structure and properties. Here authors uncover formate defects in MOF-74 that originate from decomposed DMF solvent. NMR shows that the defects partially eliminate open metal sites and lead to a decrease of gas adsorption; the adsorption mechanism of CO2 in defective MOF is also elucidated.
- Yao Fu
- , Yifeng Yao
- & Xueqian Kong
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Article
| Open AccessCharacterization of a fold in TANGO1 evolved from SH3 domains for the export of bulky cargos
The authors characterized a fold in the TANGO1 protein which evolved from SH3 domains for the export of bulky cargos such as collagen. They denote this fold as MOTH (MIA, Otoraplin, TALI/TANGO1 homology) domain.
- Oliver Arnolds
- & Raphael Stoll
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Article
| Open AccessTurning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase
Using a combination of MD simulations and NMR, the authors investigate how temperature affects allostery in imidazole glycerol phosphate synthase (IGPS), revealing that increase of temperature triggers local amino acid dynamics and providing insights into mechanism of allosteric regulation.
- Federica Maschietto
- , Uriel N. Morzan
- & Victor S. Batista
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Article
| Open AccessFunction and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor
Intrinsically disordered regions of GPCRs have been understudied for their role in receptor signaling. Here, Jie Heng et al. reveal the dynamic behavior of β2 adrenergic receptor C-terminus and its autoinhibitory function in downstream Gs coupling.
- Jie Heng
- , Yunfei Hu
- & Brian K. Kobilka
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Article
| Open AccessUnequivocal identification of two-bond heteronuclear correlations in natural products at nanomole scale by i-HMBC
The inability to distinguish two-bond from long-range HMBC correlation has historically impeded NMR structure elucidation. Here the authors developed a practical iHMBC methodology utilizing accurate isotope shift measurement to overcome this limitation.
- Yunyi Wang
- , Aili Fan
- & Xiao Wang
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Article
| Open AccessStructural conservation of HBV-like capsid proteins over hundreds of millions of years despite the shift from non-enveloped to enveloped life-style
Nackednaviruses and hepatitis B virus (HBV) have a common non-enveloped viral ancestor. While HBV acquired an envelope during evolution, nackednaviruses remained non-enveloped. Here, Pfister et al. apply CryoEM and NMR to characterize the capsid structure of African cichlid nackednavirus (ACNDV) at pH 5.5 and pH 7.5 and show that the capsid structure is very similar to that of HBV.
- Sara Pfister
- , Julius Rabl
- & Beat H. Meier
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Article
| Open AccessRobust automated backbone triple resonance NMR assignments of proteins using Bayesian-based simulated annealing
The authors present BARASA, an approach to assign backbone triple resonance spectra of proteins that augments traditional approaches with a Bayesian statistical analysis of the observed chemical shifts. The algorithm employs a simulated annealing engine to establish a consensus set of resonance assignments and is tested against systems ranging in size to over 450 amino acids including examples of intrinsically disordered proteins.
- Anthony C. Bishop
- , Glorisé Torres-Montalvo
- & A. Joshua Wand
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Article
| Open AccessThe architecture of transmembrane and cytoplasmic juxtamembrane regions of Toll-like receptors
Toll-like receptors (TLRs) play a key role in the innate immune system. Here, Kornilov et al. resolve the 3D structures of the membrane-associated parts of four TLRs to reveal properties of the juxta-membrane domain.
- F. D. Kornilov
- , A. V. Shabalkina
- & K. S. Mineev
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Article
| Open AccessDecrypting the programming of β-methylation in virginiamycin M biosynthesis
Biosynthesis of complex polyketides by polyketide synthases often relies on trans-acting enzymes to modify the intermediates. Here, the authors elucidate how β-methylation enzymes identify their substrates. The recognition is imperfect, resulting in a doubly β-methylated virginiamycin derivative.
- Sabrina Collin
- , Russell J. Cox
- & Arnaud Gruez
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Article
| Open AccessIntermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery
Understanding of GPCR activation is limited as the structural information fails to present the full spectrum of energy landscape. Here, authors establish a series of conformation-biased mutants that represent five conformational states lying along adenosine A2A receptor (A2AR) activation.
- Xudong Wang
- , Chris Neale
- & Libin Ye
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Article
| Open AccessStructural basis of HIV-1 maturation inhibitor binding and activity
HIV maturation inhibitors such as bevirimat (BVM) interfering with Gag processing are emerging as alternative anti-retroviral drug candidates. Here, the authors report structures of assemblies of HIV-1 Gag fragments spanning the CA C-terminal domain and SP1 region bound to BVM.
- Sucharita Sarkar
- , Kaneil K. Zadrozny
- & Tatyana Polenova
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Article
| Open AccessVisible light-exposed lignin facilitates cellulose solubilization by lytic polysaccharide monooxygenases
Degradation of plant biomass, comprised of cellulose and polyaromatic lignin, is promoted by light. Here, the authors show that light promotes lignin-catalyzed generation of hydrogen peroxide, which is used by redox enzymes to degrade cellulose.
- Eirik G. Kommedal
- , Camilla F. Angeltveit
- & Vincent G. H. Eijsink
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Article
| Open AccessA bivalent remipede toxin promotes calcium release via ryanodine receptor activation
Insect toxins with tandem repeats of neurotoxin domains have been found with enhanced receptor avidity. Here, the authors describe a bivalent toxin from remipede venom that targets ryanodine receptors, a rare target for animal venoms.
- Michael J. Maxwell
- , Chris Thekkedam
- & Mehdi Mobli
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Article
| Open AccessAnionic phospholipids control mechanisms of GPCR-G protein recognition
In cell membranes, lipids are ubiquitous regulators of protein function. Here, Thakur et al. observe anionic phospholipids impact the conformational dynamics of a class A human GPCR.
- Naveen Thakur
- , Arka P. Ray
- & Matthew T. Eddy
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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 AccessTwo distinct binding modes provide the RNA-binding protein RbFox with extraordinary sequence specificity
Here the authors show that the RRM of RbFox accomplishes extraordinary sequence specificity by employing functionally and structurally distinct binding modes - one for its cognate RNA and one for all non-cognate RNAs.
- Xuan Ye
- , Wen Yang
- & Fan Yang
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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 AccessAtlas of plasma NMR biomarkers for health and disease in 118,461 individuals from the UK Biobank
The authors report a systematic analyses of blood biomarkers for metabolism against the whole spectrum of diseases in 100,000 individuals and reveals a prominent role of numerous metabolic biomarkers as risk markers beyond heart disease and diabetes.
- Heli Julkunen
- , Anna Cichońska
- & Peter Würtz
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Article
| Open AccessMolecular elucidation of drug-induced abnormal assemblies of the hepatitis B virus capsid protein by solid-state NMR
Hepatitis B virus (HBV) capsid assembly modulators (CAM) represent a recent class of anti-HBV antivirals. Structural approaches provide limited conformational information on the CAM-induced off-path assemblies. Here, authors use solid-state NMR to establish a structural view on assembly modulation of the HBV capsid.
- Lauriane Lecoq
- , Louis Brigandat
- & Anja Böckmann
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Article
| Open AccessMetamorphism in TDP-43 prion-like domain determines chaperone recognition
In this work, the authors show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease and stress the relevance of post-translationally modified chains as the targets for disease intervention.
- Jaime Carrasco
- , Rosa Antón
- & Javier Oroz
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Article
| Open AccessDesign and characterization of a protein fold switching network
In this work the authors investigate the structure-sequence dependance. The ability to design and characterize proteins at interfaces between three common folds suggests that fold switching is an intrinsic feature of protein folding language and likely important in the evolution of protein structure and function.
- Biao Ruan
- , Yanan He
- & Philip N. Bryan
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Article
| Open AccessBiomolecular condensates formed by designer minimalistic peptides
The molecular mechanisms underlying the formation of biomolecular condensates have not been fully elucidated. Here the authors show that the LLPS propensity, dynamics, and encapsulation efficiency of designed peptide condensates can be tuned by subtle changes to the peptide composition.
- Avigail Baruch Leshem
- , Sian Sloan-Dennison
- & Ayala Lampel
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Article
| Open AccessStructural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma
BRD4-NUT’s bipartite binding and activation of p300 in NUT carcinoma nucleates a feed-forward spread of histone hyperacetylation and chromatin condensation that sustains aberrant pro-proliferation gene transcription and perpetual tumor cell growth.
- Di Yu
- , Yingying Liang
- & Lei Zeng
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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 AccessUnderstanding the failure process of sulfide-based all-solid-state lithium batteries via operando nuclear magnetic resonance spectroscopy
All-solid-state lithium batteries performance is affected by the solid electrolyte interphase (SEI) and electrically disconnected (“dead”) Li metal. Here, via operando NMR measurements, the authors quantify the Li metal in the SEI and “dead” regions using various inorganic solid-state electrolytes.
- Ziteng Liang
- , Yuxuan Xiang
- & Yong Yang
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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 AccessStructural insights into p300 regulation and acetylation-dependent genome organisation
Here the authors use structural analyses to show that an intrinsically disordered transcription activation domain in the oncogene BRD4-NUT binds to and activates p300. This in-turn drives formation of higher-order, acetylation-dependent chromatin condensates.
- Ziad Ibrahim
- , Tao Wang
- & Daniel Panne
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Article
| Open AccessVisualizing the transiently populated closed-state of human HSP90 ATP binding domain
To refold client proteins, HSP90 chaperone undergoes large structural rearrangements. Here the authors use NMR and molecular simulation and reveal structure and dynamics of a key functionally relevant metastable state of human HSP90α N-terminal domain.
- Faustine Henot
- , Elisa Rioual
- & Jerome Boisbouvier
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Article
| Open AccessChemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors
Heparin is a family of complex carbohydrates binding to proteins to modulate cell activities. Here the authors report the synthesis, and conformations simulations of S-linked hemi-A heparosan [GlcA-S-GlcNAc]n, a thio-glycosidic uncleavable polysaccharide, and test it as human heparanase inhibitor.
- Peng He
- , Xing Zhang
- & Paul L. DeAngelis
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Article
| Open AccessShedding light on the base-pair opening dynamics of nucleic acids in living human cells
Base-pair opening is important for nucleic acids to exert biological functions, but studying its dynamics inside living cells is challenging. Here, the authors determine the base-pair opening kinetics of hairpin and G-quadruplex structures inside living human cells by the in-cell NMR technique, and demonstrate a difference in dynamics of nucleic acids between in-cell and in vitro conditions.
- Yudai Yamaoki
- , Takashi Nagata
- & Masato Katahira
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Article
| Open AccessHydrophobicity of arginine leads to reentrant liquid-liquid phase separation behaviors of arginine-rich proteins
Arginine-rich proteins display reentrant LLPS behavior with changes in salt and temperature due to the hydrophobicity of arginine. Controlling the reentrant LLPS behavior opens avenues for the bioengineering and drug delivery fields.
- Yuri Hong
- , Saeed Najafi
- & Dong Soo Hwang
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Article
| Open AccessPredicting protein function and orientation on a gold nanoparticle surface using a residue-based affinity scale
The orientation of proteins on nanoparticle surfaces is important to the nanoparticle’s fate in vivo. Here, the authors use competitive binding between protein variants to develop a residue-based affinity scale to develop a model for the binding and orientation of proteins on gold nanoparticles
- Joanna Xiuzhu Xu
- , Md. Siddik Alom
- & Nicholas C. Fitzkee
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Article
| Open AccessSampling of structure and sequence space of small protein folds
In this work the authors provide a computational workflow for the parallel, from scratch, design of proteins to rapidly explore the shape diversity of protein folds.
- Thomas W. Linsky
- , Kyle Noble
- & Eva-Maria Strauch
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Article
| Open AccessA glutamine-based single α-helix scaffold to target globular proteins
Targeting biomedically relevant protein-protein interactions is a long-lasting challenge in medicinal chemistry. Here, the authors develop a single α-helical peptide scaffold that can be tailored to target globular proteins of biomedical interest.
- Albert Escobedo
- , Jonathan Piccirillo
- & Xavier Salvatella
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Article
| Open AccessA redox switch regulates the assembly and anti-CRISPR activity of AcrIIC1
Here, the authors report the discovery of a redox switch for AcrIIC1, which regulates AcrIIC1’s monomer-dimer interconversion and inhibitory activity on Cas9. By reporting the structures of different redox states of NmeAcrIIC1, they identify a pair of conserved cysteines which mediate the redox switch. The replacement of the redox-sensitive cysteines allows the generation of a more stable and robust variant under various cellular environments.
- Yanan Zhao
- , Jiaojiao Hu
- & Fan Yang
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Article
| Open AccessIncreased slow dynamics defines ligandability of BTB domains
Here, the authors discover that ligandability of BTB domains correlates with the presence of μs-ms time scale dynamics. This finding suggests that protein dynamics may be a broadly applicable tool in drug discovery to assess the ligandability of novel and challenging targets.
- Vladlena Kharchenko
- , Brian M. Linhares
- & Łukasz Jaremko
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Article
| Open AccessThe 3D structure of lipidic fibrils of α-synuclein
Interactions between α-synuclein fibrils and lipids have been associated with the development of Parkinson’s disease. This cryo-EM study reveals structural details of these interactions and suggests a mechanism for fibril-induced lipid extraction.
- Benedikt Frieg
- , Leif Antonschmidt
- & Gunnar F. Schröder
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Article
| Open AccessMagic-angle-spinning NMR structure of the kinesin-1 motor domain assembled with microtubules reveals the elusive neck linker orientation
In this work the authors report the structure of nucleotide-free kinesin-1 motor domain (apo-KIF5B) in complex with paclitaxel-stabilized microtubules using magic-angle-spinning (MAS) NMR spectroscopy. The study provides insights into the dynamic changes under which the neck linker goes upon binding to ADP.
- Chunting Zhang
- , Changmiao Guo
- & Tatyana Polenova
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Article
| Open AccessJuxtaposition of Bub1 and Cdc20 on phosphorylated Mad1 during catalytic mitotic checkpoint complex assembly
Formation of the mitotic checkpoint complex (MCC) is catalysed by a phosphorylation-dependent scaffold. This work provides structural details of how a tripartite Mad1:Bub1:Cdc20 complex presents Cdc20 to Mad2, triggering open-to-closed conversion of Mad2 to assemble the MCC.
- Elyse S. Fischer
- , Conny W. H. Yu
- & David Barford
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Article
| Open AccessAtomic resolution protein allostery from the multi-state structure of a PDZ domain
In this manuscript the authors report accurate multi-state protein structures of the PDZ domain using biological NMR. By looking into protein structural states, the authors report an allosteric pathway at atomic resolution that validates previously reported low resolution findings and uncovered a structural hallmark of the allosteric ligand binding to the PDZ domain.
- Dzmitry Ashkinadze
- , Harindranath Kadavath
- & Roland Riek