Interactome3D: adding structural details to protein networks

Journal name:
Nature Methods
Year published:
Published online


Network-centered approaches are increasingly used to understand the fundamentals of biology. However, the molecular details contained in the interaction networks, often necessary to understand cellular processes, are very limited, and the experimental difficulties surrounding the determination of protein complex structures make computational modeling techniques paramount. Here we present Interactome3D, a resource for the structural annotation and modeling of protein-protein interactions. Through the integration of interaction data from the main pathway repositories, we provide structural details at atomic resolution for over 12,000 protein-protein interactions in eight model organisms. Unlike static databases, Interactome3D also allows biologists to upload newly discovered interactions and pathways in any species, select the best combination of structural templates and build three-dimensional models in a fully automated manner. Finally, we illustrate the value of Interactome3D through the structural annotation of the complement cascade pathway, rationalizing a potential common mechanism of action suggested for several disease-causing mutations.

At a glance


  1. The Interactome3D pipeline.
    Figure 1: The Interactome3D pipeline.

    The pipeline starts from either a user-provided list of interactions or a list of organisms for which it automatically compiles the most complete binary interactome. Experimental structures are collected and homology models built for both single interactors and binary complexes. Experimental structures are collected from the PDB, and homology models for single proteins are downloaded from Modbase. Models for interactions are built using Modeller starting from either global templates from the PDB or domain-domain templates from 3did.

  2. Structural coverage of proteins and interactions for eight organisms.
    Figure 2: Structural coverage of proteins and interactions for eight organisms.

    (a) Structural coverage of the single proteins in the binary interactomes. Coloring indicates the availability of complete experimental structures (green), complete models (yellow) or only partial models (orange). (b) Structural coverage of the binary interactions. Green, interactions for which an experimental structure is available; yellow and orange, interactions for which a homology model can be built from either a global template or a domain-domain template, respectively.

  3. Benchmarking of the homology models of interactions generated by Interactome3D.
    Figure 3: Benchmarking of the homology models of interactions generated by Interactome3D.

    (a,b) Classification of homology models generated by Interactome3D for interactions already having an experimental structure, shown in absolute numbers (a) and as percentages within a given organism (b). High, medium, acceptable and incorrect correspond to the quality criteria used by CAPRI for the evaluation of protein-protein docking predictions.

  4. Structural annotation of the complement cascade.
    Figure 4: Structural annotation of the complement cascade.

    Shown is the complement cascade pathway from KEGG (pathway ID hsa04610, inset) annotated with all the structural data collected by Interactome3D. For some of the proteins only partial models are available. We also mapped mutations related to three different diseases onto the collected structures and classified them as buried in the core of the proteins (circle), on the surface (star on the structure of a protein) or at an interface between two proteins (star on the line connecting two proteins). Mutations that could not be mapped onto the structure of the protein are represented with squares. Symbols of mutations are colored according to the disease to which they belong.

  5. Mapping disease mutations in the context of the structural interactome.
    Figure 5: Mapping disease mutations in the context of the structural interactome.

    Shown are complement C3 and CFH (right) and their interactions (left) either within the complement cascade (light blue) or taken from the human interactome (gray). Although VSIG4 is not in the KEGG pathway for the complement cascade, it is shown in blue because it is known to be a potent inhibitor of the complement pathway convertases42, 43. Onto this interaction neighborhood we have mapped mutations for ten diseases (see key, top left) and classified them as either buried in the core of the protein (circles) or exposed on the surface (stars). Stars on a line between two proteins refer to mutations found at an interface. The two circular insets show the mapping of nine mutations related to hemolitic uremic syndrome atypical onto two different experimental structures (PDB 2XQW and 2WII) of the interaction between CFH (orange) and C3 (blue). Mutated residues are shown in atomic surface representation and colored red. Although the mutations belong to two different proteins, most are located on the same interaction interfaces, and these may all act by affecting the binding between the two proteins. One mutated residue (Cys1158, in green) belongs to the interacting domain A2M_comp of C3 and is buried inside the domain instead of being exposed on the interaction interface with CFH.

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Author information


  1. Joint IRB-BSC Program in Computational Biology, Institute for Research in Biomedicine, Barcelona, Spain.

    • Roberto Mosca,
    • Arnaud Céol &
    • Patrick Aloy
  2. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.

    • Patrick Aloy


R.M. conceived and designed the work, wrote the manuscript, developed the pipeline, analyzed the data and implemented the Interactome3D web resource. A.C. compiled the integrated interaction database used by Interactome3D and implemented the Interactome3D web resource. P.A. conceived the work and wrote the manuscript.

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Supplementary information

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    Supplementary Figs. 1–3, Supplementary Tables 1, 2 and 4

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  1. Supplementary Table 3 (659 KB)

    Structures used for the structural annotation of the Complement Cascade pathway

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