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Open Access Highly Accessed Research article

Identification of recurring protein structure microenvironments and discovery of novel functional sites around CYS residues

Shirley Wu12, Tianyun Liu3 and Russ B Altman234*

Author Affiliations

1 23andMe, 1390 Shorebird Way, Mountain View, CA, USA

2 Program in Biomedical Informatics, Stanford University, Palo Alto, CA, USA

3 Department of Genetics, Stanford University, Palo Alto, CA, USA

4 Department of Bioengineering, Stanford University, Palo Alto, CA, USA

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BMC Structural Biology 2010, 10:4  doi:10.1186/1472-6807-10-4

Published: 2 February 2010



The emergence of structural genomics presents significant challenges in the annotation of biologically uncharacterized proteins. Unfortunately, our ability to analyze these proteins is restricted by the limited catalog of known molecular functions and their associated 3D motifs.


In order to identify novel 3D motifs that may be associated with molecular functions, we employ an unsupervised, two-phase clustering approach that combines k-means and hierarchical clustering with knowledge-informed cluster selection and annotation methods. We applied the approach to approximately 20,000 cysteine-based protein microenvironments (3D regions 7.5 Å in radius) and identified 70 interesting clusters, some of which represent known motifs (e.g. metal binding and phosphatase activity), and some of which are novel, including several zinc binding sites. Detailed annotation results are available online for all 70 clusters at webcite.


The use of microenvironments instead of backbone geometric criteria enables flexible exploration of protein function space, and detection of recurring motifs that are discontinuous in sequence and diverse in structure. Clustering microenvironments may thus help to functionally characterize novel proteins and better understand the protein structure-function relationship.