Protein design articles within Nature Chemistry

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  • News & Views |

    Expansion of the genetic code can enable precise manipulation of proteins through selective functionalization of specific residues. Now, control of tryptophan interactions in proteins can be established by encoding of a vinyl-caged tryptophan analogue that can be selectively decaged to rescue protein activity.

    • Aidan K. Haney
    •  & T. Ashton Cropp

  • Article |

    Developing a generalizable method for blocking and rescuing tryptophan (Trp) interactions would enable the gain-of-function manipulation of various Trp-containing proteins but has so far been challenging. Now a genetically encoded N1-vinyl-caged Trp capable of rapid and bioorthogonal decaging enables site-specific activation of Trp on a protein of interest within living cells.

    • Yuchao Zhu
    • , Wenlong Ding
    •  & Peng R. Chen

  • News & Views |

    Recent improvements in de novo protein design are likely to support a broad range of applications, but larger complexes will be easier to create if a building block approach is adopted. Now protein filaments with tunable geometry can be made using assemblies that have both cyclic and superhelical symmetries aligned along the same axis.

    • Jeremy R. H. Tame

  • Article
    | Open Access

    Molecular systems with coincident cyclic and superhelical symmetry axes have considerable advantages for materials design as they can be lengthened or shortened by changing the length of the monomers. Now a systematic approach to generate modular repeat protein oligomers with combined symmetry that can be extended by repeat propagation has been developed.

    • Neville P. Bethel
    • , Andrew J. Borst
    •  & David Baker

  • Article
    | Open Access

    Three-protein conjugates, which have so far been produced using protein-engineering strategies, can now be generated using a chemical approach that enables the addition of small-molecule functionality. Checkpoint inhibitory T cell engagers (CiTEs) were assembled and shown to have enhanced in vitro potency compared to a traditional T cell engager.

    • Peter A. Szijj
    • , Melissa A. Gray
    •  & Vijay Chudasama

  • Article
    | Open Access

    Allostery produces concerted functions of protein complexes by orchestrating the cooperative work between the constituent subunits. By restoring functions of pseudo-active sites that have been lost through evolution, allosteric sites have now been designed into a rotary molecular motor, V1-ATPase, resulting in its rotation being boosted allosterically.

    • Takahiro Kosugi
    • , Tatsuya Iida
    •  & Nobuyasu Koga

  • Article |

    Microtubules carry patterns of post-translational modifications that are important for the regulation of key cellular processes. Now a semi-synthetic method facilitates the production of tubulins with defined post-translational modifications. Using these designer tubulins, polyglutamylation of α-tubulin is found to promote its detyrosination by enhancing the activity of the carboxypeptidase vasohibin/small vasohibin-binding protein.

    • Eduard Ebberink
    • , Simon Fernandes
    •  & Charlotte Aumeier

  • Article |

    Incorporating polar residues into hydrophobic protein channel pores facilitates selective proton transport. Now, classical and multiscale reactive molecular dynamics simulations of designed channels reveal dynamic water wires within the channel lumen that are proton conductive according to structural and functional validation. These results provide some guiding principles for biological and engineered proton conduction.

    • Huong T. Kratochvil
    • , Laura C. Watkins
    •  & William F. DeGrado

  • News & Views |

    From humans designing machines, to machines designing biology, deep learning is turning the tables for assisted exploration of biologically active and diverse protein designs. Now, a deep-learning-based strategy has been used to design artificial enzymes that catalyse a light-emitting reaction.

    • Christian Dallago
    •  & Kevin K. Yang

  • News & Views |

    Designing membrane proteins that function as ion channels is challenging. Now, peptides that self-assemble into water-soluble α-helical barrels have been repurposed to form ion channels in membranes by lining the interior with polar residues and the exterior with hydrophobic ones.

    • Giovanna Ghirlanda

  • Article |

    Collagen-like peptides can self-assemble into hundreds of closely related triple helices. Now, an algorithm has been developed that predicts the most stable helix and the extent to which it will assemble to the exclusion of the competing helices. This information can help improve the understanding of triple helix design and assembly.

    • Douglas R. Walker
    • , Sarah A. H. Hulgan
    •  & Jeffrey D. Hartgerink

  • Article |

    A de novo designed zinc-binding protein has been converted into a highly active, stereoselective catalyst for a hetero-Diels–Alder reaction. Design and directed evolution were used to effectively harness Lewis acid catalysis and create an enzyme more proficient than other reported Diels–Alderases.

    • Sophie Basler
    • , Sabine Studer
    •  & Donald Hilvert

  • Article |

    A method to fabricate heterotrimeric three-stranded coiled-coil peptide structures has now been developed using coordination around a Pb(ii) centre. The heterotrimeric structures require only three cysteines that bind to Pb(ii) to form a trigonal pyramidal structure, and the formation of an adjacent cavity in which water can hydrogen bond to the cysteine sulfur atoms.

    • Audrey E. Tolbert
    • , Catherine S. Ervin
    •  & Vincent L. Pecoraro

  • Perspective |

    The complexity of proteins has inspired chemists to seek artificial mimetics of protein structure and function. Historically, most such work has focused on analogues of small, isolated segments; however, there is growing interest in mimicry of larger, intact tertiary folds. This Perspective surveys the emerging body of work on these agents, termed ‘proteomimetics’, discusses their construction and outlines some of the remaining challenges.

    • W. Seth Horne
    •  & Tom N. Grossmann

  • News & Views |

    Nature harnesses fractal geometry to create structures with unusual surface-to-volume ratios. Now, a new design approach enables the reversible assembly of functional enzymes into arboreal patterns with fractal geometry.

    • Iris D. Young
    •  & James S. Fraser

  • Article |

    A concise strategy for engineering functional, supramolecular protein complexes has now been developed based on single-mutation-mediated covalent tethering. Metalloproteins designed with this method can sustain large alterations to the metal coordination environment, bind small molecules, exhibit reversible redox activity and sustain large alterations to the protein structure.

    • Jonathan Rittle
    • , Mackenzie J. Field
    •  & F. Akif Tezcan

  • Article |

    Proteins have the potential to serve as powerful scaffolds that control the catalytic activity and selectivity of organometallic centres; however, new methods are needed to optimize artificial metalloenzymes. Now, an efficient approach for evolving the activity and selectivity of artificial metalloenzymes has been demonstrated using dirhodium cyclopropanases. This approach does not require structural or mechanistic data to guide mutagenesis.

    • Hao Yang
    • , Alan M. Swartz
    •  & Jared C. Lewis

  • Perspective |

    Glucose-responsive insulin is a therapeutic that modulates its potency, concentration or dosing relative to a patient’s dynamic glucose concentration. This Perspective summarizes some of the recent accomplishments in this field as well as discussing new computational algorithms that may aid in the development of such therapeutics.

    • Naveed A. Bakh
    • , Abel B. Cortinas
    •  & Michael S. Strano

  • Article |

    The first demonstration of a protein designed entirely from first principles that binds a small-molecule cofactor in a precisely predetermined orientation has now been described. The design method utilizes a remote protein core that both anchors and predisposes a flexible binding site for the desired cofactor-binding geometry.

    • Nicholas F. Polizzi
    • , Yibing Wu
    •  & William F. DeGrado

  • News & Views |

    Two papers provide insight into the reactivity of cytochrome P450s. A direct link between electron donation and reactivity has been shown with a selenocysteine-ligated P450 compound I, whereas a serine-ligated P450 (P411) has been engineered to catalyse an intermolecular C–H amination via nitrene transfer.

    • Rudi Fasan

  • 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 |

    Despite decades of research into heme-copper oxidases, the advantages provided by copper over iron as the non-heme metal has remained unclear. Now, the preference of copper over iron has finally been explained. Copper favours faster electron transfer and higher O–O bond activation, which results in much higher oxidase activity than would be achieved by an iron equivalent.

    • Ambika Bhagi-Damodaran
    • , Matthew A. Michael
    •  & Yi Lu

  • Article |

    A protein-only redox film inspired by the architecture of bacterial electroactive biofilms has been developed. The film is formed using a rubredoxin–prion domain chimeric protein. The prion domains self-assemble into fibres that are decorated with rubredoxin. This results in highly organized films, able to transport electrons over several microns, and wire enzymes to electrodes.

    • Lucie Altamura
    • , Christophe Horvath
    •  & Vincent Forge

  • Article |

    An artificial aldolase has been optimized using an ultrahigh-throughput microfluidic screening assay. The evolved enzyme exhibits excellent stereoselectivity and broad substrate scope. Structural studies suggest that a Lys-Tyr-Asn-Tyr catalytic tetrad, which emerged during directed evolution, is responsible for the >109 rate enhancement achieved by this catalyst.

    • Richard Obexer
    • , Alexei Godina
    •  & Donald Hilvert

  • News & Views |

    An artificial esterase with no known natural structural analogues has been formed via the homo-heptameric self-assembly of a designed peptide. This esterase represents the first report of a functional catalytic triad rationally engineered into a de novo protein framework.

    • Olga V. Makhlynets
    •  & Ivan V. Korendovych

  • Article |

    A motif was identified in the scaffold of an (S)-selective transaminase that enables the asymmetric synthesis of bulky chiral amines. This motif is transferable to other enzymes with as low as 70% sequence identity. The biocatalysts developed show high stereoselectivity and their synthetic potential was confirmed in preparative scale synthesis.

    • Ioannis V. Pavlidis
    • , Martin S. Weiß
    •  & Uwe T. Bornscheuer

  • Article |

    Functional catalytic triads have been designed into a hyperstable heptameric α-helical barrel protein. Twenty-one mutations were introduced to form seven Cys-His-Glu catalytic triads. The resulting protein hydrolyses p-nitrophenyl acetate with activities matching the most-efficient redesigned hydrolases based on natural protein scaffolds. This is the first example of a functional catalytic triad being engineered into a fully de novo protein.

    • Antony J. Burton
    • , Andrew R. Thomson
    •  & Derek N. Woolfson

  • Article |

    S-Nitrosylation has emerged as an important pathway for dynamic post-translational regulation of many classes of proteins. Now, the reversible insertion of NO into a copper–thiolate bond has been observed under physiologically relevant conditions using an engineered azurin. DFT calculation indicates that the reaction proceeds via a radical combination mechanism.

    • Shiliang Tian
    • , Jing Liu
    •  & Yi Lu

  • Article |

    Nature's speciality is to direct and control the reactivity of species, which are otherwise fatally destructive. However, the processes and design rules required to achieve such precise control are not clear. A de novo designed metalloprotein that stabilizes an otherwise unstable organic radical has now been developed to guide our understanding.

    • Gözde Ulas
    • , Thomas Lemmin
    •  & William F. DeGrado

  • News & Views |

    A dramatic switch of reactivity — from hydroquinone oxidation to N-hydroxylation — can be achieved through the rational engineering of a de novo-designed di-iron protein. Four specific amino-acid mutations spread throughout the first, second and third coordination shells result in a million-fold increase in the relative rate of these two reactions.

    • Steven M. Berry

  • Article |

    Representing the first successful rational reprogramming of function in a de novo protein, the reactivity of a designed di-iron carboxylate protein from the Due Ferri family was altered from hydroquinone oxidation to arylamine N-hydroxylation through the introduction of a critical third histidine ligand in the active site.

    • Amanda J. Reig
    • , Marcos M. Pires
    •  & William F. DeGrado

  • Article |

    Multiple redox reaction pathways exist in proteins containing several cysteines. A technique termed mechanical uncaging is now demonstrated, allowing the release of a single reactive cysteine within a protein and the unequivocal observation of subsequent thiol/disulfide exchanges. Mechanical uncaging of reactive groups is useful for studying chemical kinetics in a synchronized manner.

    • Jorge Alegre-Cebollada
    • , Pallav Kosuri
    •  & Julio M. Fernández

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