Protein-protein interactions are essential for life. Yet, our understanding of the general principles governing binding is not complete. In the present study, we show that the interface between proteins is built in a modular fashion; each module is comprised of a number of closely interacting residues, with few interactions between the modules. The boundaries between modules are defined by clustering the contact map of the interface. We show that mutations in one module do not affect residues located in a neighboring module. As a result, the structural and energetic consequences of the deletion of entire modules are surprisingly small. To the contrary, within their module, mutations cause complex energetic and structural consequences. Experimentally, this phenomenon is shown on the interaction between TEM1-beta-lactamase and beta-lactamase inhibitor protein (BLIP) by using multiple-mutant analysis and x-ray crystallography. Replacing an entire module of five interface residues with Ala created a large cavity in the interface, with no effect on the detailed structure of the remaining interface. The modular architecture of binding sites, which resembles human engineering design, greatly simplifies the design of new protein interactions and provides a feasible view of how these interactions evolved.
PDB ID: 1S0WDownload
MMDB ID: 26591
PDB Deposition Date: 2004/1/5
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Streptomyces clavuligerus
Similar Structures:
Biological Unit for 1S0W: dimeric; determined by author and by software (PISA)
Molecular Components in 1S0W
Label Count Molecule
Proteins (2 molecules)
Beta-lactamase TEM
Molecule annotation
Beta-lactamase Inhibitory Protein
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB