Structural biology articles within Nature Chemistry

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  • News & Views |

    Single-particle cryo-electron microscopy and all-atom molecular dynamics simulations provide atomic details of ATP hydrolysis in the multimeric enzyme p97.

    • Nadia Elghobashi-Meinhardt

  • Article
    | Open Access

    The human ATP-hydrolysing enzyme p97 populates a metastable reaction intermediate, the ADP·Pi state, which is poised between hydrolysis and product release. Now, molecular motions at the active site in the temporal window immediately before and after ATP hydrolysis have been elucidated by merging cryo-EM, NMR spectroscopy and molecular dynamics simulations.

    • Mikhail Shein
    • , Manuel Hitzenberger
    •  & Anne K. Schütz

  • Article |

    Many natural products are produced by non-ribosomal peptide synthetases in an assembly-line fashion. How these molecular machines orchestrate the biochemical sequences has remained elusive. It is now understood that an extended-conformation ensemble is needed to coordinate chemical-transformation steps whereas the biosynthesis directionality is driven by the enzyme’s innate conformational free energies.

    • Xun Sun
    • , Jonas Alfermann
    •  & Haw Yang

  • Research Briefing |

    An infrared laser-induced temperature jump provides a rapid and broadly applicable perturbation to protein dynamics. Temperature-jump crystallography was paired with time-resolved X-ray crystallography to study the dynamic enzyme lysozyme. Measurements with and without a functional inhibitor revealed different patterns in the propagation of motion throughout the enzyme.

  • Article
    | Open Access

    Shifts in temperature alter the structure and dynamics of macromolecules. Now, infra-red laser-induced temperature jump is combined with X-ray crystallography to observe protein structural dynamics in real time. Using this method, motions related to the catalytic cycle of lysozyme, a model enzyme, are visualized at atomic resolution and across broad timescales.

    • Alexander M. Wolff
    • , Eriko Nango
    •  & Michael C. Thompson

  • Article
    | Open Access

    Pump–probe measurements conventionally achieve femtosecond time resolution for X-ray crystallography of reactive processes, but the measured structural dynamics are complex. Using coherent control techniques, we show that the ultrafast crystallographic differences of a fluorescent protein are dominated by ground-state vibrational processes that are unconnected to the photoisomerization reaction of the chromophore.

    • Christopher D. M. Hutchison
    • , James M. Baxter
    •  & Jasper J. van Thor

  • News & Views |

    Tandem cycloaddition reactions have significant applications in organic synthetic chemistry. Now, two enzymes are shown to catalyse tandem hetero-Diels–Alder reactions with a synergistic interplay between a calcium cofactor and N-glycan post-translational modifications during the biosynthesis of bistropolone-sesquiterpene secondary metabolites.

    • Richiro Ushimaru
    •  & Ikuro Abe

  • Article |

    Most chemoproteomic screening approaches are indirect. Now, a chemoproteomic platform based on chiral sulfonyl fluoride probes has been developed for the direct identification of probe-modified tyrosines and lysines in live cells. Stereoselective modification by structurally diverse probes was observed for 634 tyrosines and lysines across functionally diverse protein sites.

    • Ying Chen
    • , Gregory B. Craven
    •  & Jack Taunton

  • News & Views |

    Genetic code expansion beyond α-amino acids is a major challenge, in which stitching together non-natural building blocks within the ribosome is a critical barrier. Now, the molecular determinants for the efficient incorporation of non-natural amino acids into the ribosome have been unlocked, accelerating ribosomal synthesis.

    • Souvik Sinha
    • , Mohd Ahsan
    •  & Giulia Palermo

  • Article
    | Open Access

    The metal-dependent, bifunctional isoprenyl diphosphate synthase PcIDS1 from the leaf beetle Phaedon cochleariae integrates substrate, product and metal-ion concentrations to tune its dynamic reactivity. Now structural and functional analyses reveal that this enzyme uses both catalytic centres to form geranyl pyrophosphate, while one domain is inactivated during farnesyl pyrophosphate production.

    • Felix Ecker
    • , Abith Vattekkatte
    •  & Michael Groll

  • Article
    | Open Access

    Genetic code expansion to incorporate non-α-amino acid monomers is limited by predictability of monomer reactivities in the context of the ribosome. Now the use of metadynamics simulations of pre-attack monomers in the ribosomal peptidyl transferase centre provides insight on whether an A-site monomer is likely to be reactive.

    • Zoe L. Watson
    • , Isaac J. Knudson
    •  & Ara M. Abramyan

  • Article
    | Open Access

    Ribosomal incorporation of non-α-amino acid monomers into proteins is largely restricted to in vitro translation. Now, pyrrolysyl-transfer RNA synthetase variants have been shown to acylate tRNAs with α-thio acids, malonic acids, and N-formyl amino acids. This work represents a key step towards the programmed ribosomal synthesis of sequence-defined non-protein polymers in cellulo.

    • Riley Fricke
    • , Cameron V. Swenson
    •  & Alanna Schepartz

  • Article |

    Cellular membranes contain numerous lipids, and efforts to understand the biological functions of individual lipids demand approaches for controlled modulation of membrane composition in situ. Now, click chemistry-based directed evolution of a microbial phospholipase within mammalian cells affords an editor for optogenetic, targeted modification of phospholipids in cell membranes.

    • Reika Tei
    • , Saket R. Bagde
    •  & Jeremy M. Baskin

  • Article
    | Open Access

    In vitro screening of a ribosomally synthesized macrocyclic peptide library containing cyclic γ2,4-amino acids (cγAA) afforded the discovery of potent inhibitors of the SARS-CoV-2 main protease (Mpro). A co-crystal structure revealed the contribution of this cγAA to Mpro binding and the proteolytic stability of these macrocycles.

    • Takashi Miura
    • , Tika R. Malla
    •  & Hiroaki Suga

  • Article
    | Open Access

    The alkaloids crocagins are derived from a ribosomal peptide through a series of enzymatic post-translational modifications. A combination of biochemistry and structural biology techniques has now been used to elucidate this biosynthetic pathway, propose a mechanism for the formation of the tetracyclic core structure and enable genome mining for related natural products.

    • Sebastian Adam
    • , Dazhong Zheng
    •  & Jesko Koehnke

  • News & Views |

    2+2-cycloaddition reactions have long been considered key transformations in the biosynthesis of cyclobutane-containing natural products, but enzymes for these reactions have not yet been identified. Now, a 2+2 cyclase has been discovered, characterized and bioengineered to catalyse cycloadditions with different selectivity.

    • Bo Zhang
    •  & Hui Ming Ge

  • Article |

    A Diels–Alderase that catalyses the inherently disfavoured cycloaddition and forms a bicyclo[2.2.2]diazaoctane scaffold with a strict α-anti-selectivity has now been discovered. This Diels–Alderase, called CtdP, is an NmrA-like protein. Isotopic labelling, structural biology and computational studies reveal that the CtdP-catalysed Diels–Alder reaction involves a NADP+/NADPH-dependent redox mechanism.

    • Zhiwen Liu
    • , Sebastian Rivera
    •  & Xue Gao

  • Article |

    Enzymes with identical sequences of amino acids can display varying activities when encoded with mRNA with different properties, but why this is the case has been a mystery. Now, it has been shown that synonymous mutations in mRNA alter the partitioning of proteins into long-lived soluble misfolded states with varying activities.

    • Yang Jiang
    • , Syam Sundar Neti
    •  & Edward P. O’Brien

  • Article |

    Synthesis of peptidyl-tRNAs is challenging because there are no enzymes that can directly attach the desired peptide to tRNA. Now it has been shown that a chemoenzymatic approach based on native chemical ligation can be used for the semi-synthesis of peptidyl-tRNAs for structural/biochemical studies of arrested and non-arrested ribosome complexes.

    • Egor A. Syroegin
    • , Elena V. Aleksandrova
    •  & Yury S. Polikanov

  • Article
    | Open Access

    Proteins rich in phenylalanine-glycine (FG) repeats can phase separate through FG–FG interactions. The molecular interactions of an important FG-repeat protein, nucleoporin 98, have now been studied in liquid-like transient and amyloid-like cohesive states. These interactions underlie the behaviour of FG-repeat proteins and their function in physiological and pathological cell activities.

    • Alain Ibáñez de Opakua
    • , James A. Geraets
    •  & Markus Zweckstetter

  • Article |

    The β1-adrenergic receptor (β1AR) contains empty cavities in its preactive conformation, which disappear in the active one. Now, using X-ray crystallography of xenon-derivatized β1AR crystals, a cavity has been shown to be in contact with the cholesterol-binding pocket. Monitoring the binding of a cholesterol analogue in solution has explained the function of cholesterol as a negative allosteric modulator of β1AR.

    • Layara Akemi Abiko
    • , Raphael Dias Teixeira
    •  & Stephan Grzesiek

  • Article
    | Open Access

    Most proteins must fold co-translationally on the ribosome to adopt biologically active conformations, yet structural, mechanistic descriptions are lacking. Using 19F NMR spectroscopy to study a nascent multi-domain protein has now enabled the identification of two co-translational folding intermediates that are significantly more stable than intermediates formed off the ribosome, suggesting that the ribosome may thermodynamically regulate folding.

    • Sammy H. S. Chan
    • , Tomasz Włodarski
    •  & John Christodoulou

  • Article |

    A genetically encoded phototrigger based on a xanthone amino acid can expand the scope of time-resolved serial femtosecond crystallography beyond naturally photoactive proteins. This approach has been used to uncover metastable reaction intermediates that occur prior to C–H bond activation in a human liver fatty-acid-binding protein mutant.

    • Xiaohong Liu
    • , Pengcheng Liu
    •  & Jiangyun Wang

  • Article |

    A reduction reaction is usually equated with an electron transfer reaction. Now, ultrafast time-resolved serial femtosecond X-ray crystallography has enabled the visualization of the stepwise structural changes that occur after electron transfers have been observed in the light-triggered reduction of flavin adenine dinucleotide catalysed by DNA photolyase.

    • Manuel Maestre-Reyna
    • , Cheng-Han Yang
    •  & Ming-Daw Tsai

  • Article |

    The complex link between protein sequence and phase behaviour for a family of prion-like low-complexity domains (PLCDs) has now been revealed. The results have uncovered a set of rules—which are interpreted using a stickers-and-spacers model—that govern the sequence-encoded phase behaviour of such PLCDs and enable physicochemical rationalizations that are connected to the underlying sequence composition.

    • Anne Bremer
    • , Mina Farag
    •  & Tanja Mittag

  • News & Views |

    Machine learning algorithms are fast surpassing human abilities in multiple tasks, from image recognition to medical diagnostics. Now, machine learning algorithms have been shown to be capable of accurately predicting the folded structures of proteins.

    • Cecilia Clementi

  • Article
    | Open Access

    During polypeptide biosynthesis, a strong interaction can occur between a segment of an emerged, disordered nascent protein and the ribosomal surface. Now, it has been shown that competition between this ribosomal binding and the folding energetics of an immunoglobulin-like domain modulates the mechanism of co-translational folding.

    • Anaïs M. E. Cassaignau
    • , Tomasz Włodarski
    •  & John Christodoulou

  • Article |

    The opening mechanism of the SARS-CoV-2 spike protein has been studied by integrating computational and experimental data. Combining weighted ensemble molecular dynamics simulations, biolayer interferometry and ManifoldEM analysis of cryo-EM data revealed that the glycan at N343 plays a gating role in the opening mechanism of the SARS-CoV-2 spike protein.

    • Terra Sztain
    • , Surl-Hee Ahn
    •  & Rommie E. Amaro

  • Article |

    Simulations of the SARS-CoV-2 proteome that include over 0.1 s of aggregate data are reported. Spike opening was observed, revealing cryptic epitopes that differ between variants, explaining differential interactions with antibodies and receptors that determine pathogenicity. The cryptic pockets described provide new targets for antivirals and a wealth of mechanistic insight.

    • Maxwell I. Zimmerman
    • , Justin R. Porter
    •  & Gregory R. Bowman

  • Article |

    RNA origami can be used for the modular design of RNA nanoscaffolds but can be challenging to design. Newly developed computer-aided design software has now been shown to improve the folding yield of kilobase-sized RNA origami. These structures fold from a single strand during transcription by an RNA polymerase, and are able to position small molecules and protein components with nanoscale precision.

    • Cody Geary
    • , Guido Grossi
    •  & Ebbe S. Andersen

  • Article |

    A chemoenzymatic method to site-specifically conjugate peptide and protein thioesters to folded proteins at lysine residues has been developed. The method uses a genetically encoded four-residue tag that is recognized by the E2 SUMO-conjugating enzyme Ubc9. This approach enables isopeptide formation with just Ubc9 in a programmable manner and obviates the need for E1 and E3 enzymes.

    • Raphael Hofmann
    • , Gaku Akimoto
    •  & Jeffrey W. Bode

  • Article |

    Cyclic β-amino acids can add useful properties to peptides, such as inducing turn structures or providing resistance to proteases. To harness these properties up to ten consecutive cyclic β-amino acids have now been ribosomally incorporated via genetic code reprogramming into a foldamer peptide library that has been screened for potent binders against a protein target, human factor XIIa.

    • Takayuki Katoh
    • , Toru Sengoku
    •  & Hiroaki Suga

  • Article |

    Class II terpene cyclases convert simple linear substrates into complex polycyclic compounds, which typically requires multiple protein domains. Now, a single-domain class II cyclase, a cyanobacterial merosterolic acid synthase, has been identified and characterized. High-resolution X-ray crystal structures provide detailed insights into how a minimalistic enzyme accomplishes this complex cyclization process.

    • Philipp Moosmann
    • , Felix Ecker
    •  & Jörn Piel

  • Article |

    The invariable core of a type II polyketide synthase has been characterized using X-ray crystallography, simulations, mutagenesis experiments and functional assays. The characterization of the ternary acyl carrier protein complexes provides a mechanistic understanding of the reactivity and could inform future engineering of this complex biosynthetic machinery.

    • Alois Bräuer
    • , Qiuqin Zhou
    •  & Michael Groll

  • Article |

    The antibiotic enacyloxin IIa is assembled by a modular polyketide synthase, and released from it by condensation of the enacyloxin acyl chain with 3,4-dihydroxycyclohexane carboxylic acid. A multipronged approach shows the structural basis for recognition between the peptidyl carrier protein domain that bears the acyl chain and the non-ribosomal peptide synthetase condensation domain that ligates it with the carboxylic acid.

    • Simone Kosol
    • , Angelo Gallo
    •  & Józef R. Lewandowski

  • Article |

    The complete biosynthesis of the fungal indole alkaloid malbrancheamide, which culminates in an intramolecular [4+2] hetero-Diels–Alder cyclization to produce the bicyclo[2.2.2]diazaoctane scaffold, has now been discovered. Chemical synthesis and protein structural analysis were used to provide mechanistic insight into this enzyme-dependent diastereo- and enantioselective cycloaddition.

    • Qingyun Dan
    • , Sean A. Newmister
    •  & Robert M. Williams

  • Article |

    Understanding how structural dynamics contribute to protein function is a longstanding challenge in structural biology. Now, time-resolved X-ray solution scattering following an infrared laser-induced temperature jump has been used to probe functional, intramolecular motions in the dynamic enzyme cyclophilin A.

    • Michael C. Thompson
    • , Benjamin A. Barad
    •  & James S. Fraser

  • Article |

    The UbiD family of reversible decarboxylases interconvert propenoic or aromatic acids with the corresponding alkenes or aromatic compounds, using a transient 1,3-dipolar cycloaddition between the substrate and the prenylated flavin mononucleotide cofactor. Atomic-resolution crystallography shows targeted destabilization of the intermediate covalent adducts, allowing the enzyme to harness 1,3-dipolar cycloaddition as a readily reversible reaction.

    • Samuel S. Bailey
    • , Karl A. P. Payne
    •  & David Leys

  • Article |

    LepI is an S-adenosylmethionine-dependent pericyclase that catalyses the dehydration, hetero-Diels–Alder reaction and retro-Claisen rearrangement reactions that occur in the formation of the 2-pyridone natural product leporin C. Now, the mechanistic details that underpin this range of catalytic reactions have been uncovered from the crystal structures of LepI and LepI in complex with ligands.

    • Yujuan Cai
    • , Yang Hai
    •  & Yi Tang

  • Article |

    Symmetrical protein oligomers perform key structural and catalytic functions in nature, but engineering such oligomers synthetically is challenging. Now, oppositely supercharged synthetic variants of normally monomeric proteins have been shown to assemble via specific, introduced electrostatic contacts into symmetrical, highly well-defined oligomers.

    • Anna J. Simon
    • , Yi Zhou
    •  & Andrew D. Ellington

  • Article |

    Inhibiting the interaction between amyloid-β (Aβ) and a neuronal cell surface receptor, LilrB2, could offer a potential route for treating Alzheimer’s disease. Now, binding sites between Aβ and LilrB2 have been discovered and computational selection has identified inhibitors that block this binding site. Cell-penetrating inhibitors were found to block the Aβ–LilrB2 interaction and limit Aβ-induced cytotoxicity.

    • Qin Cao
    • , Woo Shik Shin
    •  & Lin Jiang

  • Article |

    An integrated native mass spectrometry and top-down proteomics method using Fourier transform ion cyclotron resonance has been developed for the characterization of macromolecular protein complexes. This approach directly yields primary to quaternary structural information in a single native top-down experiment.

    • Huilin Li
    • , Hong Hanh Nguyen
    •  & Joseph A. Loo

  • Article |

    Tau aggregation is associated with Alzheimer's disease and dozens of related dementias. Now atomic structures of the aggregation-prone segment VQIINK in repeat 2 of tau have been reported. Inhibitors designed using these structures block seeding by full-length tau better than inhibitors that target the VQIVYK aggregation segment in repeat 3.

    • P. M. Seidler
    • , D. R. Boyer
    •  & D. S. Eisenberg

  • Article |

    Providing detailed structural descriptions of the ultrafast photochemical events that occur in light-sensitive proteins is key to their understanding. Now, excited-state structures in the reversibly switchable fluorescent protein rsEGFP2 have been solved by time-resolved crystallography using an X-ray laser. These structures enabled the design of a mutant with improved photoswitching quantum yields.

    • Nicolas Coquelle
    • , Michel Sliwa
    •  & Martin Weik

  • Review Article |

    Recent years have witnessed a surge of interest in targeted covalent inhibition of disease-associated proteins. Among the electrophiles used to interact with nucleophilic residues in protein structures, boron is unique for its chameleonic ability to display a range of coordination modes upon interaction with protein targets.

    • Diego B. Diaz
    •  & Andrei K. Yudin

  • Article |

    Several natural and unnatural lissoclimide cytotoxins have been prepared via semi-synthesis and total synthesis. An X-ray co-crystal structure of chlorolissoclimide with the ribosome and evaluation of cytotoxicity and translation inhibition of new compounds in the series improves our understanding of the molecular basis for cytotoxicity.

    • Zef A. Könst
    • , Anne R. Szklarski
    •  & Christopher D. Vanderwal

  • Article |

    Berkelium is the only transplutonium element predicted to be able to exhibit both +III and +IV oxidation states in solution. Bk(IV) has now been stabilized through chelation with a siderophore derivative. The resulting neutral coordination compound was characterized and compared with the negatively charged species obtained by chelation of neighbouring trivalent actinides.

    • Gauthier J.-P. Deblonde
    • , Manuel Sturzbecher-Hoehne
    •  & Rebecca J. Abergel

  • Article |

    A computational method to design cyclic protein homo-oligomers has been developed. Using this approach, a series of idealized repeat proteins incorporating designed interfaces that direct their assembly into complexes possessing cyclic symmetry were fabricated. 15 out of 96 oligomers that were characterized experimentally were shown to be consistent with the computational model.

    • Jorge A. Fallas
    • , George Ueda
    •  & David Baker

  • Article |

    Off-target drug binding of anti-HIV protease inhibitors to a zinc metalloprotease has been suspected for some time. Now, mass spectrometry of human zinc metalloprotease ZMPSTE24 in the presence of four inhibitors has provided molecular evidence for this off-target binding. These results also enabled an investigation of the effects of the inhibitors on the processing of farnesylated prelamin A peptides.

    • Shahid Mehmood
    • , Julien Marcoux
    •  & Carol V. Robinson

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