Inspired by nature

Netzer, Ravit; Fleishman, Sarel J.

doi:10.1126/science.aaf7599

Cited by 9 publications

(5 citation statements)

References 10 publications

(6 reference statements)

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“…Such cooperative interaction networks do not typically arise in conventional antibody affinity-maturation processes (either in nature or the laboratory), which select mutations in a stepwise manner and are therefore biased towards additive rather than cooperative multipoint mutations. Introducing accurate new polar interaction networks is also a fundamental challenge for computational design [53,54] and the use of evolutionary constraints during design has recently been shown to overcome this challenge [42].…”

Section: Resultsmentioning

confidence: 99%

Optimizing antibody affinity and stability by the automated design of the variable light-heavy chain interfaces

et al. 2019

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Antibodies developed for research and clinical applications may exhibit suboptimal stability, expressibility, or affinity. Existing optimization strategies focus on surface mutations, whereas natural affinity maturation also introduces mutations in the antibody core, simultaneously improving stability and affinity. To systematically map the mutational tolerance of an antibody variable fragment (Fv), we performed yeast display and applied deep mutational scanning to an anti-lysozyme antibody and found that many of the affinity-enhancing mutations clustered at the variable light-heavy chain interface, within the antibody core. Rosetta design combined enhancing mutations, yielding a variant with tenfold higher affinity and substantially improved stability. To make this approach broadly accessible, we developed AbLIFT, an automated web server that designs multipoint core mutations to improve contacts between specific Fv light and heavy chains ( http://AbLIFT.weizmann.ac.il ). We applied AbLIFT to two unrelated antibodies targeting the human antigens VEGF and QSOX1. Strikingly, the designs improved stability, affinity, and expression yields. The results provide proof-of-principle for bypassing laborious cycles of antibody engineering through automated computational affinity and stability design.

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Section: Resultsmentioning

confidence: 99%

Optimizing antibody affinity and stability by the automated design of the variable light-heavy chain interfaces

et al. 2019

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“…First, the design is moving from structural to functional models. While it is still challenging to control protein folding and assembly in structural protein design [223], recent efforts have been made to design of functional metalloenzymes, aimed at achieving high efficiency and selectivity [152]. In these attempts, various approaches have been developed, such as substituting the metal ion [65], creating new metalbinding site [173], and exploiting directed evolutions [37,52,54,55,224,225].…”

Section: Conclusion and Perspectivementioning

confidence: 99%

“…Third, the design is moving from using natural to unnatural components, including abiological metals [54] and clusters [124], UAAs [77][78][79], and de novo protein scaffolds [33,69]. Although only helical bundles have been extensively exploited for de novo metalloenzymes design, much progress has been made in controlling protein folding and assembly [222,223,226,227], and fully de novo designed protein structures, even beyond those found in Nature [228], are expected in design of functional metalloenzymes. The utilization of these diverse unnatural components will certainly overcome the limitations for natural metalloenzymes, and expand the functionalities of designed metalloenzymes beyond the repertoire of natural enzymes [37].…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Rational design of metalloenzymes: From single to multiple active sites

Lin

2017

Coordination Chemistry Reviews

132

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Artificial metalloenzymes combine the advantages of both natural enzymes and chemically synthesized models, which have achieved significant progress in the last decade. This review summarizes the recent achievements in rational design of metalloenzymes from single to multiple active sites in natural or de novo protein scaffolds, with a diverse range of functionalities, even beyond those of natural metalloenzymes. These achievements include construction of mononuclear active site by metal substitution or incorporation, design of homo-or hetero-dinuclear site, introduction of Fe-sulfur or other metal clusters, reconstitution of metallo-porphyrins or other metal complexes, and design of dual or multiple active sites in single, dimeric proteins, de novo proteins, protein-protein interfaces, as well as protein oligomers and polymers. Other new trends in recent designs are also discussed. The progress not only elucidates the structural and functional relationship of natural metalloenzymes, but also provides practical clues for design of advanced artificial metalloenzymes with potential applications.

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“…12 New and readily accessible/quantifiable biomarkers are required to help identifying the underlying reasons in individual patients, and consequently adapt immune therapy strategies in order to increase patient survival. 13 …”

Section: Introductionmentioning

confidence: 99%

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

et al. 2018

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Increased density of tumor-associated lymphatic vessels correlates with poor patient survival in melanoma and other cancers, yet lymphatic drainage is essential for initiating an immune response. Here we asked whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes (LNs) from patients with cutaneous melanoma. Using immunohistochemistry and quantitative image analysis, we found significant positive correlations between LVD and CD8+ T cell infiltration as well as expression of the immunosuppressive molecules inducible nitric oxide synthase (iNOS) and 2,3-dioxygénase (IDO). Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating loco-regional effects of tumors. Our data suggest that lymphatic vessels play multiple roles at tumor sites and LNs, promoting both T cell infiltration and adaptive immunosuppressive mechanisms. Lymph vessel associated T cell infiltration may increase immunotherapy success rates provided that the treatment overcomes adaptive immune resistance.

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Inspired by nature

Abstract: Designed proteins have structural features resembling those of natural active sites

Cited by 9 publications

References 10 publications

Optimizing antibody affinity and stability by the automated design of the variable light-heavy chain interfaces

Optimizing antibody affinity and stability by the automated design of the variable light-heavy chain interfaces

Rational design of metalloenzymes: From single to multiple active sites

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

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Inspired by nature

Abstract: Designed proteins have structural features resembling those of natural active sites

Cited by 9 publications

References 10 publications

Optimizing antibody affinity and stability by the automated design of the variable light-heavy chain interfaces

Optimizing antibody affinity and stability by the automated design of the variable light-heavy chain interfaces

Rational design of metalloenzymes: From single to multiple active sites

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

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Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma