1. Structural Biology and Molecular Biophysics
  2. Computational and Systems Biology
Download icon

Codon-level information improves predictions of inter-residue contacts in proteins by correlated mutation analysis

  1. Etai Jacob
  2. Ron Unger
  3. Amnon Horovitz  Is a corresponding author
  1. Bar-Ilan University, Israel
  2. Weizmann Institute of Science, Israel
Research Article
  • Cited 5
  • Views 2,805
  • Annotations
Cite this article as: eLife 2015;4:e08932 doi: 10.7554/eLife.08932


Methods for analysing correlated mutations in proteins are becoming an increasingly powerful tool for predicting contacts within and between proteins. Nevertheless, limitations remain due to the requirement for large multiple sequence alignments (MSA) and the fact that, in general, only the relatively small number of top-ranking predictions are reliable. To date, methods for analysing correlated mutations have relied exclusively on amino acid MSAs as inputs. Here, we describe a new approach for analysing correlated mutations that is based on combined analysis of amino acid and codon MSAs. We show that a direct contact is more likely to be present when the correlation between the positions is strong at the amino acid level but weak at the codon level. The performance of different methods for analysing correlated mutations in predicting contacts is shown to be enhanced significantly when amino acid and codon data are combined.

Article and author information

Author details

  1. Etai Jacob

    The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Ron Unger

    The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Amnon Horovitz

    Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Michael Levitt, Stanford University, United States

Publication history

  1. Received: May 22, 2015
  2. Accepted: September 13, 2015
  3. Accepted Manuscript published: September 15, 2015 (version 1)
  4. Accepted Manuscript updated: September 25, 2015 (version 2)
  5. Version of Record published: October 13, 2015 (version 3)


© 2015, Jacob et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


  • 2,805
    Page views
  • 568
  • 5

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Structural Biology and Molecular Biophysics
    Fangyu Liu et al.
    Research Article Updated

    The ATP-binding cassette (ABC) transporter family contains thousands of members with diverse functions. Movement of the substrate, powered by ATP hydrolysis, can be outward (export) or inward (import). ABCA4 is a eukaryotic importer transporting retinal to the cytosol to enter the visual cycle. It also removes toxic retinoids from the disc lumen. Mutations in ABCA4 cause impaired vision or blindness. Despite decades of clinical, biochemical, and animal model studies, the molecular mechanism of ABCA4 is unknown. Here, we report the structures of human ABCA4 in two conformations. In the absence of ATP, ABCA4 adopts an outward-facing conformation, poised to recruit substrate. The presence of ATP induces large conformational changes that could lead to substrate release. These structures provide a molecular basis to understand many disease-causing mutations and a rational guide for new experiments to uncover how ABCA4 recruits, flips, and releases retinoids.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Manoj K Rathinaswamy et al.
    Research Article

    Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110g) playing key roles in immune signalling. p110g is a key factor in inflammatory diseases, and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall this work provides unique insights into regulatory mechanisms that control PI3Kg kinase activity, and shows a framework for the design of PI3K isoform and mutant selective inhibitors.