Limits...
Protein functional surfaces: global shape matching and local spatial alignments of ligand binding sites.

Binkowski TA, Joachimiak A - BMC Struct. Biol. (2008)

Bottom Line: Surfaces performing identical functions are found in proteins absent of any sequence or fold similarity.Results using surface similarity to predict function for proteins of unknown function are reported.Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA. abinkowski@anl.gov

ABSTRACT

Background: Protein surfaces comprise only a fraction of the total residues but are the most conserved functional features of proteins. Surfaces performing identical functions are found in proteins absent of any sequence or fold similarity. While biochemical activity can be attributed to a few key residues, the broader surrounding environment plays an equally important role.

Results: We describe a methodology that attempts to optimize two components, global shape and local physicochemical texture, for evaluating the similarity between a pair of surfaces. Surface shape similarity is assessed using a three-dimensional object recognition algorithm and physicochemical texture similarity is assessed through a spatial alignment of conserved residues between the surfaces. The comparisons are used in tandem to efficiently search the Global Protein Surface Survey (GPSS), a library of annotated surfaces derived from structures in the PDB, for studying evolutionary relationships and uncovering novel similarities between proteins.

Conclusion: We provide an assessment of our method using library retrieval experiments for identifying functionally homologous surfaces binding different ligands, functionally diverse surfaces binding the same ligand, and binding surfaces of ubiquitous and conformationally flexible ligands. Results using surface similarity to predict function for proteins of unknown function are reported. Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.

Show MeSH
An all-against-all comparison of ATP binding surfaces in the PDB. The dendrogram represents the results of complete-linkage clustering, applied to SurfaceScreen score between all surfaces in our dataset (a). The nodes of the dendrogram are color coded for kinase families according to KinBase nomenclature. A branch of the cluster (gray box) is called-out to highlight the unexpected similarity discovered between the STI-571 binding site in c-Abl kinase and serine/threonine kinase p38 MAP (b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2626596&req=5

Figure 14: An all-against-all comparison of ATP binding surfaces in the PDB. The dendrogram represents the results of complete-linkage clustering, applied to SurfaceScreen score between all surfaces in our dataset (a). The nodes of the dendrogram are color coded for kinase families according to KinBase nomenclature. A branch of the cluster (gray box) is called-out to highlight the unexpected similarity discovered between the STI-571 binding site in c-Abl kinase and serine/threonine kinase p38 MAP (b).

Mentions: An all-against-all comparison was performed with results used to populate a distance matrix of SurfaceScreen scores. A dendrogram showing the complete-linkage clustering is shown in Figure 14 where each surface node is color coded by kinase subfamily. Overall, the method shares strong agreement with the annotated classification, as seen by the color banding. CDK2 kinases are the most ordered; with all members perfectly clustered together and distinct sub-grouping separating nucleotide ligands from small compound inhibitors. The CK2 and CAMP families also show divergence between natural ligands and inhibitors. The CAMP groupings are further clustered by the molecular weight of their bound ligands. The mitogen activated protein kinases (MAP) are successfully classified into their sub-families, but on distant nodes in the graph. In all families, we observe differentiation based on the activation state of the kinase.


Protein functional surfaces: global shape matching and local spatial alignments of ligand binding sites.

Binkowski TA, Joachimiak A - BMC Struct. Biol. (2008)

An all-against-all comparison of ATP binding surfaces in the PDB. The dendrogram represents the results of complete-linkage clustering, applied to SurfaceScreen score between all surfaces in our dataset (a). The nodes of the dendrogram are color coded for kinase families according to KinBase nomenclature. A branch of the cluster (gray box) is called-out to highlight the unexpected similarity discovered between the STI-571 binding site in c-Abl kinase and serine/threonine kinase p38 MAP (b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2626596&req=5

Figure 14: An all-against-all comparison of ATP binding surfaces in the PDB. The dendrogram represents the results of complete-linkage clustering, applied to SurfaceScreen score between all surfaces in our dataset (a). The nodes of the dendrogram are color coded for kinase families according to KinBase nomenclature. A branch of the cluster (gray box) is called-out to highlight the unexpected similarity discovered between the STI-571 binding site in c-Abl kinase and serine/threonine kinase p38 MAP (b).
Mentions: An all-against-all comparison was performed with results used to populate a distance matrix of SurfaceScreen scores. A dendrogram showing the complete-linkage clustering is shown in Figure 14 where each surface node is color coded by kinase subfamily. Overall, the method shares strong agreement with the annotated classification, as seen by the color banding. CDK2 kinases are the most ordered; with all members perfectly clustered together and distinct sub-grouping separating nucleotide ligands from small compound inhibitors. The CK2 and CAMP families also show divergence between natural ligands and inhibitors. The CAMP groupings are further clustered by the molecular weight of their bound ligands. The mitogen activated protein kinases (MAP) are successfully classified into their sub-families, but on distant nodes in the graph. In all families, we observe differentiation based on the activation state of the kinase.

Bottom Line: Surfaces performing identical functions are found in proteins absent of any sequence or fold similarity.Results using surface similarity to predict function for proteins of unknown function are reported.Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA. abinkowski@anl.gov

ABSTRACT

Background: Protein surfaces comprise only a fraction of the total residues but are the most conserved functional features of proteins. Surfaces performing identical functions are found in proteins absent of any sequence or fold similarity. While biochemical activity can be attributed to a few key residues, the broader surrounding environment plays an equally important role.

Results: We describe a methodology that attempts to optimize two components, global shape and local physicochemical texture, for evaluating the similarity between a pair of surfaces. Surface shape similarity is assessed using a three-dimensional object recognition algorithm and physicochemical texture similarity is assessed through a spatial alignment of conserved residues between the surfaces. The comparisons are used in tandem to efficiently search the Global Protein Surface Survey (GPSS), a library of annotated surfaces derived from structures in the PDB, for studying evolutionary relationships and uncovering novel similarities between proteins.

Conclusion: We provide an assessment of our method using library retrieval experiments for identifying functionally homologous surfaces binding different ligands, functionally diverse surfaces binding the same ligand, and binding surfaces of ubiquitous and conformationally flexible ligands. Results using surface similarity to predict function for proteins of unknown function are reported. Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.

Show MeSH