ArticleNature2013
Computational design of ligand-binding proteins with high affinity and selectivity.
Article in Nature, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 196 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
196 citing papers in PubMed, 446 citations in OpenAlex.
- Mapping subcellular microenvironments using oligonucleotide-directed proximity labeling.Current opinion in chemical biology · 2026Review
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- Emergence of specific binding and catalysis from a designed generalist binding protein.Nature chemistry · 2026Article
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- Small-molecule binding and sensing with a designed protein family.Nature communications · 2026Article
- FoTO1 orchestrates Taxol biosynthesis through catalytic and non-catalytic mechanisms.bioRxiv : the preprint server for biology · 2026Article
- HCR-Proxy resolves site-specific proximal RNA microenvironments at subcompartmental resolution.Nucleic acids research · 2026Article
- Synthetic Biology of Plants and Microbes for Agriculture, Environment, and Future Applications.Chemical reviews · 2026Review
- Engineering mammalian protein secretion: Toward the convergence of high-throughput biology and computational methods.Cell systems · 2025Review
- Buttressing ligand-binding pockets in de novo designed NTF2-like domains.Protein science : a publication of the Protein Society · 2025Article
- Protein Design Meets Single-Molecule Detection: Towards Programmable Nanopore Sensors.International journal of molecular sciences · 2025Review
- Enhanced hybridization-proximity labeling discovers protein interactomes of single RNA molecules.Nature communications · 2025Article
- The open-source Masala software suite: Facilitating rapid methods development for synthetic heteropolymer design.bioRxiv : the preprint server for biology · 2025Article
- Rapid clearance of achiral small-molecule drugs using de novo-designed proteins and their cyclic and mirror-image variants.Nature biomedical engineering · 2025Article
- Variant scoring tools for deep mutational scanning.Molecular systems biology · 2025Review
- A cell-free biosensor signal amplification circuit with polymerase strand recycling.Nature chemical biology · 2025Article
- Assembly and Functionality of 2D Protein Arrays.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Design of nanobody targeting SARS-CoV-2 spike glycoprotein using CDR-grafting assisted by molecular simulation and machine learning.PLoS computational biology · 2025Article
- Article
136 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
The ability to design proteins with high affinity and selectivity for any given small molecule is a rigorous test of our understanding of the physiochemical principles that govern molecular recognition. Attempts to rationally design ligand-binding proteins have met with little success, however, and the computational design of protein-small-molecule interfaces remains an unsolved problem. Current approaches for designing ligand-binding proteins for medical and biotechnological uses rely on raising antibodies against a target antigen in immunized animals and/or performing laboratory-directed evolution of proteins with an existing low affinity for the desired ligand, neither of which allows complete control over the interactions involved in binding. Here we describe a general computational method for designing pre-organized and shape complementary small-molecule-binding sites, and use it to generate protein binders to the steroid digoxigenin (DIG). Of seventeen experimentally characterized designs, two bind DIG; the model of the higher affinity binder has the most energetically favourable and pre-organized interface in the design set. A comprehensive binding-fitness landscape of this design, generated by library selections and deep sequencing, was used to optimize its binding affinity to a picomolar level, and X-ray co-crystal structures of two variants show atomic-level agreement with the corresponding computational models. The optimized binder is selective for DIG over the related steroids digitoxigenin, progesterone and β-oestradiol, and this steroid binding preference can be reprogrammed by manipulation of explicitly designed hydrogen-bonding interactions. The computational design method presented here should enable the development of a new generation of biosensors, therapeutics and diagnostics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.