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| Open AccessStructural basis for ion selectivity revealed by high-resolution crystal structure of Mg2+ channel MgtE
MgtE is a magnesium ion-selective channel conserved in all domains of life that contributes to the maintenance of cellular Mg2+homeostasis. Here, the authors provide high-resolution crystal structures of MgtE combined with biochemical analyses that reveal the molecular basis for selectivity.
- Hironori Takeda
- , Motoyuki Hattori
- & Osamu Nureki
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Multiple enzymatic activities of ParB/Srx superfamily mediate sexual conflict among conjugative plasmids
Conjugative plasmids block translocation of rival plasmids using fertility inhibition factors (FINs). Here Maindola et al.present the structure of the FIN Osa and show that it contains a ParB/Sulfiredoxin fold with both ATPase and DNase activity, with general functional implications for this fold.
- Priyank Maindola
- , Rahul Raina
- & Arulandu Arockiasamy
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| Open AccessA critical base pair in k-turns that confers folding characteristics and correlates with biological function
The k-turn is a widespread RNA element that adopts a kinked structure that mediates tertiary contacts and frequently binds specific proteins. Here, McPhee et al. show that the ability of a given k-turn to fold in the presence of metal ions alone—or to otherwise require protein binding—is attributable to a specific base pair.
- Scott A. McPhee
- , Lin Huang
- & David M. J. Lilley
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Article
| Open AccessOn the absence of intrahelical DNA dynamics on the μs to ms timescale
No experimental evidence exists for intra-helical motion of DNA at the μs timescale, which has been attributed to technical difficulties in observing motion in this time range. Here, the authors demonstrate, using extensive molecular dynamics simulations and experimental analysis, that such motion is effectively absent from a B-DNA duplex.
- Rodrigo Galindo-Murillo
- , Daniel R. Roe
- & Thomas E. Cheatham III
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Protein design with a comprehensive statistical energy function and boosted by experimental selection for foldability
Methods to design proteins de novo can give insights into how amino acids fold into particular structures and aid in protein engineering. Here, Xiong et al. compare a novel statistical energy function with established methods and use it to generate four de novoproteins.
- Peng Xiong
- , Meng Wang
- & Haiyan Liu
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A general mechanism for competitor-induced dissociation of molecular complexes
Departure of ligands from cell surfaces can be slowed by rapid rebinding to nearby receptors. Here, the authors use single-molecule experiments and theory to show that rapid rebinding also can slow dissociation of an isolated molecular complex, allowing binding competitors to significantly raise dissociation rates.
- Thayaparan Paramanathan
- , Daniel Reeves
- & Jeff Gelles
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Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy
Understanding the molecular basis of receptor activation requires characterizing the dynamic equilibrium of conformational states. Here the authors show that the metabotropic glutamate receptor oscillates between conformations on a sub-millisecond timescale, and agonists quantitatively shift the equilibrium towards the activated state based on their potency.
- Linnea Olofsson
- , Suren Felekyan
- & Emmanuel Margeat
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| Open AccessLateral opening of the bacterial translocon on ribosome binding and signal peptide insertion
Integral membrane proteins laterally partition from the SecYEG translocon into the phospholipid bilayer. Here, the authors use photo-induced electron transfer to show that ribosome binding induces the opening of the lateral gate, and demonstrate that lateral opening does not happen at low temperature.
- Yan Ge
- , Albena Draycheva
- & Wolfgang Wintermeyer
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The X-ray crystal structure of the euryarchaeal RNA polymerase in an open-clamp configuration
Archaeal and eukaryotic RNA polymerases (RNAP) have conserved functional and structural similarities. Here, Jun et al.solve the first structure of a euryarchaeal RNAP in the open clamp conformation and identify insertions that may have evolved in eukaryotic Pol II to bind unique transcription factors.
- Sung-Hoon Jun
- , Akira Hirata
- & Katsuhiko S. Murakami
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Proof of dual-topology architecture of Fluc F− channels with monobody blockers
Fluc-type channels—used by microorganisms to extrude toxic fluoride ions—have been suggested to adopt an unusual antiparallel topology across the membrane. Stockbridge et al.now provide the best evidence so far for this atypical arrangement, showing that specific monobodies block channel activity from both sides of the membrane.
- Randy B. Stockbridge
- , Akiko Koide
- & Shohei Koide
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Unravelling the mechanism of non-ribosomal peptide synthesis by cyclodipeptide synthases
Cyclodipeptide synthases hijack aminoacyl tRNAs to produce various cyclic dipeptides—the biosynthetic precursors of several secondary metabolites. Here, the authors solved the crystal structure of a cyclodipeptide synthase bound to a reaction intermediate analogue and provide novel insights into the mechanism of synthesis.
- Mireille Moutiez
- , Emmanuelle Schmitt
- & Muriel Gondry
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High-resolution structure of the Shigella type-III secretion needle by solid-state NMR and cryo-electron microscopy
Solving structures of large protein complexes remains a significant challenge for structural biologists. Demers et al. determine the atomic structure of a Shigellatype-III secretion system using a Rosetta-based modelling strategy that draws on both solid-state NMR and cryo-electron microscopy data sets.
- Jean-Philippe Demers
- , Birgit Habenstein
- & Nikolaos G. Sgourakis
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Molecular basis of transmembrane beta-barrel formation of staphylococcal pore-forming toxins
Pore-forming toxins secreted by pathogenic bacteria attack target cells by forming openings that span the plasma membrane. Here, Yamashita et al. shed light on the mechanism of pore assembly by solving the crystal structures of two staphylococcal toxins in their prepore conformations.
- Daichi Yamashita
- , Takaki Sugawara
- & Min Yao
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Conformational flexibility and changes underlying activation of the SUMO-specific protease SENP1 by remote substrate binding
The SUMO-specific protease SENP1 is activated by binding of its substrate, SUMO1, to a site remote from the catalytic cleft. Chen et al. characterise the dynamic changes in SENP1 conformation associated with substrate binding, and reveal how they influence the catalytic activity of the enzyme.
- Chih-Hong Chen
- , Andrew T. Namanja
- & Yuan Chen
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Article
| Open AccessXTACC3–XMAP215 association reveals an asymmetric interaction promoting microtubule elongation
chTOG, a microtubule polymerase, interacts with TACC3 during mitosis to regulate spindle formation. By studying their Xenopus homologues, Mortuza et al. discover that one TACC3 recruits two chTOG molecules to the spindle, increasing its local concentration and promoting microtubule elongation.
- Gulnahar B. Mortuza
- , Tommaso Cavazza
- & Guillermo Montoya
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Article
| Open AccessStructural basis for biomolecular recognition in overlapping binding sites in a diiron enzyme system
The ability of a protein to interact with multiple other proteins is an intriguing problem. Here, the authors use crystallography to show how a diiron hydroxylase achieves two distinct steps in the catalytic reaction, by using an overlapping binding site to recognize two different binding partners.
- Justin F. Acheson
- , Lucas J. Bailey
- & Brian G. Fox
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Structural analyses of Ca2+/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation
Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells and mutations at NaV loci are responsible for several human diseases. Here, Wang et al. provide novel structural insights into the regulation of NaVchannel activity by calcium-bound calmodulin.
- Chaojian Wang
- , Ben C. Chung
- & Geoffrey S. Pitt
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Article
| Open AccessUnexpected structure for the N-terminal domain of hepatitis C virus envelope glycoprotein E1
Hepatitis C virus (HCV) gains entry into host cells via envelope glycoproteins E1 and E2. Here, El Omari et al.present the crystal structure of the N terminus of the E1 ectodomain of HCV and show that it adopts a different fold than predicted.
- Kamel El Omari
- , Oleg Iourin
- & David I. Stuart
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Conserved and host-specific features of influenza virion architecture
Influenza-infected cells produce viral particles that incorporate a mixture of viral and host proteins. Here the authors analyse by mass spectrometry the protein composition of such particles and show that the host species determines certain characteristics of an otherwise conserved architecture.
- Edward C. Hutchinson
- , Philip D. Charles
- & Ervin Fodor
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Structure of a bacterial α2-macroglobulin reveals mimicry of eukaryotic innate immunity
Alpha-2-macroglobulins are protease inhibitors that function as part of eukaryotic innate immunity. Here, Wong and Dessen solve structures of Salmonella alpha-2-macroglobulin and show that it probably serves as part of a rudimentary bacterial immune system in a similar way to the eukaryotic counterpart.
- Steve G. Wong
- & Andréa Dessen
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Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1
The RhoGEF GEF-H1 is normally sequestered on microtubules via binding dynein light-chain Tctex-1, and is activated by microtubule depolymerization. Here, Meiri et al. describe a new model of GEF-H1 activation by GPCRs, whereby both the Gα and Gβγ subunits bind to GEF-H1 and Tctex-1, respectively, to displace GEF-H1 from intact microtubules.
- David Meiri
- , Christopher B. Marshall
- & Robert Rottapel
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A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase
Subtilase SUB1, a proteolytic enzyme required for the exit of malarial parasites from host cells, represents a promising target for anti-malarial drugs. Here, Giganti et al. report the structure of PlasmodiumSUB1 and identify an essential domain involved in calcium-dependent activation of the enzyme.
- David Giganti
- , Anthony Bouillon
- & Jean-Christophe Barale
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| Open AccessCrystal structure of a common GPCR-binding interface for G protein and arrestin
G-protein-coupled receptors (GPCRs) transmit signals through intracellular heterotrimeric G proteins and arrestins. Here, Szczepek et al.present the structure of a common binding interface for Gα and arrestin on rhodopsin to shed light on key interactions that mediate transduction of specific signals through a single GPCR.
- Michal Szczepek
- , Florent Beyrière
- & Patrick Scheerer
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Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase
3-Ketoacyl-ACP reductase is required for mitochondrial fatty acid synthesis. Venkatesan et al.present structures of this enzyme, show that the β-subunit is involved in fatty acid synthesis and propose a role for the α-subunit in routing unsaturated fatty acids into β-oxidation.
- Rajaram Venkatesan
- , Shiv K. Sah-Teli
- & Zhijun Chen
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Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway
The crystal structure of the A2A GPCR suggested that water molecules might form a continuous pathway that becomes disrupted during receptor activation. Here Yuan et al.instead show that a conserved layer of hydrophobic residues forms a gate that opens to form a continuous water channel upon receptor activation.
- Shuguang Yuan
- , Slawomir Filipek
- & Horst Vogel
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| Open AccessAn atomic model of brome mosaic virus using direct electron detection and real-space optimization
Recent developments in cryo-electron microscopy have enabled structure determination of large protein complexes at almost atomic resolution. Wang et al.combine some of these technologies into an effective workflow, and demonstrate the protocol by solving the atomic structure of an icosahedral RNA virus.
- Zhao Wang
- , Corey F. Hryc
- & Wah Chiu
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Widespread transient Hoogsteen base pairs in canonical duplex DNA with variable energetics
Hoogsteen (HG) base pairs occur transiently within DNA and exhibit altered non Watson–Crick (WC)-pairing geometries with the potential to govern sequence-dependent DNA processes. Here, Alvey et al.show that HG base pairing occurs within diverse sequence contexts and define the energetic landscapes that favour WC-to-HG transitions.
- Heidi S. Alvey
- , Federico L. Gottardo
- & Hashim M. Al-Hashimi
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Structure and mechanism of action of the hydroxy–aryl–aldehyde class of IRE1 endoribonuclease inhibitors
Modulation of the unfolded protein response by targeting IRE1 has several potential therapeutic applications. Here, the authors provide a first structural view of inhibitors engaging the RNase-active site of IRE1 that suggests avenues towards the generation of analogues with increased potency and selectivity.
- Mario Sanches
- , Nicole M. Duffy
- & Frank Sicheri
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Crystal structure and its bearing towards an understanding of key biological functions of EpCAM
Epithelial cell adhesion protein (EpCAM) is a cell–cell adhesion molecule that is often used as a cancer cell marker. Here, Pavšič et al.solve the structure of a dimer of the extracellular domain of EpCAM, explain several aspects of its biology and comment on the antigenicity of its epitopes.
- Miha Pavšič
- , Gregor Gunčar
- & Brigita Lenarčič
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ATP-induced electron transfer by redox-selective partner recognition
Some biological reactions can require thermodynamically unfavourable electron transfer processes, the occurrence of which are not yet fully understood. Here, the authors provide the structural basis of energy transduction during the reductive activation of B12-dependent methyltransferases.
- Sandra E. Hennig
- , Sebastian Goetzl
- & Holger Dobbek
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General rules for the arrangements and gating motions of pore-lining helices in homomeric ion channels
Rearrangements of the pore-lining helix (PLH) bundles of ion channels are central to their gating mechanisms. Here, Dai et al. use a modelling approach to define the general rules that govern the arrangements and gating motions of the PLHs in homomeric ion channels.
- Jian Dai
- & Huan-Xiang Zhou
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Article
| Open AccessProton-coupled sugar transport in the prototypical major facilitator superfamily protein XylE
Glucose transporters are a medically important class of membrane proteins often deregulated in diseases such as Type 2 diabetes. Here, Wisedchaisri et al. report the crystal structure of XylE in an inward-facing open conformation to provide a general mechanism of substrate transport for the sugar porter family of proteins.
- Goragot Wisedchaisri
- , Min-Sun Park
- & Tamir Gonen
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Determination of tyrosinase substrate-binding modes reveals mechanistic differences between type-3 copper proteins
Tyrosinases mediate the initial two catalytic steps in the conversion of tyrosine into melanin, and mutations in these enzymes are leading causes of albinism. Goldfeder et al.present tyrosinase crystal structures and reveal that both of its substrates orient identically in the active site.
- Mor Goldfeder
- , Margarita Kanteev
- & Ayelet Fishman
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| Open AccessRetrieving the intracellular topology from multi-scale protein mobility mapping in living cells
Numerous obstacles posed by cellular subcompartments and structures constrain protein transport in the cell. Here, Baum et al.map the intracellular topology from a diffusing protein’s point of view by measuring the diffusive movements of fluorescently labelled reporter proteins in living cells on multiple time and length scales.
- Michael Baum
- , Fabian Erdel
- & Karsten Rippe
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A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites
The malaria parasite uses the methylerythritol phosphate (MEP) pathway to synthesize crucial isoprenoid metabolites. Here the authors identify and characterize a sugar phosphatase that regulates the MEP pathway by indirectly regulating the levels of isoprenoid precursors.
- Ann M. Guggisberg
- , Jooyoung Park
- & Audrey R. Odom
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| Open AccessA gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase
How the substrate specificity of fatty aldehyde dehydrogenase (FALDH) towards long-chain aldehydes is achieved is an unresolved question. Here the authors present a crystal structure of human membrane-bound FALDH and find that it contains a ‘gatekeeper’ helix that directs substrate specificity towards long-chain fatty aldehydes.
- Markus A. Keller
- , Ulrich Zander
- & Jose A. Marquez
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The highly conserved domain of unknown function 1792 has a distinct glycosyltransferase fold
Two glycosyltransferase folds have been reported, GT-A and GT-B. Here, Zhang et al.report a 1.34 Å resolution structure of a domain of unknown function that adopts a new glycosylation fold, and show that the protein functions as a glycosyltransferase.
- Hua Zhang
- , Fan Zhu
- & Hui Wu
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Article
| Open AccessImpact of residues remote from the catalytic centre on enzyme catalysis of copper nitrite reductase
Residues within the catalytic site of enzymes are important for activity, but whether more distant residues are also sensitive to mutation is unclear. Here, Leferink et al.show that mutation of residues in copper nitrate reductase that are 12Å away from the active site perturb enzyme function.
- Nicole G. H. Leferink
- , Svetlana V. Antonyuk
- & S. Samar Hasnain
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Substrate-bound outward-open state of the betaine transporter BetP provides insights into Na+ coupling
The Na+-coupled betaine transporter BetP is representative of a structural superfamily of symporters, for which different conformational states of the transport cycle are described. Perez et al.provide a structure for the elusive substrate-bound outward-open state, and propose a mechanism for sodium-coupled transport.
- Camilo Perez
- , Belinda Faust
- & Christine Ziegler
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Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs
Antagonists of Smoothened, a class F GPCR involved in the hedgehog pathway, have been developed to treat some cancers. Here Wang et al.report structures of Smoothened in complex with antagonists and an agonist, and describe how mutations may result in resistance to anti-Smoothened treatment.
- Chong Wang
- , Huixian Wu
- & Raymond C. Stevens
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Article
| Open AccessA hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel
K2P potassium channels have a structure dissimilar to other potassium channels. Here, the authors study the K2P channel TWIK-1 and show that the protein contains a deep pore hydrophobic barrier that blocks ion channel conductance.
- Prafulla Aryal
- , Firdaus Abd-Wahab
- & Stephen J. Tucker
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Article
| Open AccessProtruding knob-like proteins violate local symmetries in an icosahedral marine virus
Some viruses are spherical particles in which protein components are organized with well-defined icosahedral and local symmetries. Here, Gipson et al. describe a unique arrangement of proteins, breaking all expected local symmetries, in particles of a marine bacterial virus.
- Preeti Gipson
- , Matthew L. Baker
- & Wah Chiu
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Article
| Open AccessStructure and mechanism of an intramembrane liponucleotide synthetase central for phospholipid biosynthesis
Cytidine-diphosphate diacylglycerol (CDP-DAG) is a central liponucleotide intermediate required for the biosynthesis of some phospholipids and is synthesized by CDP-DAG synthetase (Cds). Here, Liu et al. report the structure of a Cds that shows how it can accept hydrophilic and hydrophobic substrates, and suggest a mechanism that requires two metal ions.
- Xiuying Liu
- , Yan Yin
- & Zhenfeng Liu
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| Open AccessStructural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4
SUMO forms flexible polymeric chains that can interact with ubiquitin ligases, such as RNF4. Here Xu et al. have used NMR spectroscopy and biochemical experiments to investigate the interaction between SUMO and RNF4, and propose a mechanism for delivery of substrates to the ubiquitination machinery.
- Yingqi Xu
- , Anna Plechanovová
- & Steve J. Matthews
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| Open AccessDynamic protein conformations preferentially drive energy transfer along the active chain of the photosystem II reaction centre
Cofactor-mediated energy and electron transfer in photosystem II occurs preferentially through one branch of the reaction centre, despite there being a symmetric path available. Here, the authors use computational methods to determine the influence of protein conformation on this selectivity.
- Lu Zhang
- , Daniel-Adriano Silva
- & Xuhui Huang
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Article
| Open AccessVisualizing active membrane protein complexes by electron cryotomography
Few tools are available to identify active membrane proteins within their native lipid environment. Here, Gold et al. report on a strategy that can be used for site-specific labelling of membrane proteins via electron cryotomography.
- Vicki A.M. Gold
- , Raffaele Ieva
- & Werner Kühlbrandt
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The palindromic DNA-bound USP/EcR nuclear receptor adopts an asymmetric organization with allosteric domain positioning
Nuclear receptors use DNA- and ligand-binding to regulate gene expression. Here, Maletta et al. report the first structural description of a full inverted repeat-bound nuclear receptor complex, which shows that the protein structure is asymmetric, despite the symmetry of the bound DNA.
- Massimiliano Maletta
- , Igor Orlov
- & Bruno P. Klaholz
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HOP2-MND1 modulates RAD51 binding to nucleotides and DNA
The HOP2-MND1 heterodimer is essential for homologous recombination. Here, Bugreev et al. analyse its mechanism of action in vitroand show that HOP2-MND1 stabilizes an active conformation of Rad51, thus triggering DNA strand exchange.
- Dmitry V. Bugreev
- , Fei Huang
- & Alexander V. Mazin
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X-ray structure of a CDP-alcohol phosphatidyltransferase membrane enzyme and insights into its catalytic mechanism
The CDP-alcohol phosphatidyltransferase family is involved in phospholipid biosynthesis. Here, Nogly et al.report the crystal structure of a bifunctional enzyme from this family, show that magnesium is required for enzymatic activity, and propose a structure-based catalytic mechanism.
- Przemyslaw Nogly
- , Ivan Gushchin
- & Margarida Archer