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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.

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Retrieval of ATP binding proteins from functionally and conformationally diverse classes. Binding surfaces representing different ATP conformational classes: cAMP- dependent kinase (PDB:1atp, a), protein kinase CK2 from Z. Mays (PDB:1a6o, b), ATP:corrinoid adenosyltransferase from S. typhimurium (PDB:1g5t, c), PurT-encoded glycinamide ribonucleotide transformylase from E. coli (PDB:1kj8, d). A superposition of the molecules from each class (f). The retrieval rate for each binding surface against the GPSS library is shown as an ROC plot in (e). The retrieval rates are calculated using the SurfaceScreen score.
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Figure 10: Retrieval of ATP binding proteins from functionally and conformationally diverse classes. Binding surfaces representing different ATP conformational classes: cAMP- dependent kinase (PDB:1atp, a), protein kinase CK2 from Z. Mays (PDB:1a6o, b), ATP:corrinoid adenosyltransferase from S. typhimurium (PDB:1g5t, c), PurT-encoded glycinamide ribonucleotide transformylase from E. coli (PDB:1kj8, d). A superposition of the molecules from each class (f). The retrieval rate for each binding surface against the GPSS library is shown as an ROC plot in (e). The retrieval rates are calculated using the SurfaceScreen score.

Mentions: ATP is a multifunctional nucleotide associated that has been classified to catalyze 58 different reactions by the Enzyme Commission (EC). In over 300 structural complexes, ATP binding is associated with domains from 45 homologous superfamilies, some sharing less than 8% sequence identity[52]. The nucleotide is quite flexible and adopts a wide range of conformations, some in less than energetically favorable states[52]. To determine the extent that conformational variability exerts on similarity searching, we conducted retrieval experiments with query surfaces binding ATP in diverse conformations: cAMP- dependent kinase (PDB:1atp) protein kinase CK2 from Z. mays (PDB:1a6o)[53], ATP:corrinoid adenosyltransferase from S. typhimurium (PDB:1g5t)[54], PurT-encoded glycinamide ribonucleotide transformylase from E. coli (PDB:1kj8)[55]. The conformations were selected by clustering all ATP molecules by their three-dimensional shape similarity (see Methods) and are shown in Figure 10.


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

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

Retrieval of ATP binding proteins from functionally and conformationally diverse classes. Binding surfaces representing different ATP conformational classes: cAMP- dependent kinase (PDB:1atp, a), protein kinase CK2 from Z. Mays (PDB:1a6o, b), ATP:corrinoid adenosyltransferase from S. typhimurium (PDB:1g5t, c), PurT-encoded glycinamide ribonucleotide transformylase from E. coli (PDB:1kj8, d). A superposition of the molecules from each class (f). The retrieval rate for each binding surface against the GPSS library is shown as an ROC plot in (e). The retrieval rates are calculated using the SurfaceScreen score.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 10: Retrieval of ATP binding proteins from functionally and conformationally diverse classes. Binding surfaces representing different ATP conformational classes: cAMP- dependent kinase (PDB:1atp, a), protein kinase CK2 from Z. Mays (PDB:1a6o, b), ATP:corrinoid adenosyltransferase from S. typhimurium (PDB:1g5t, c), PurT-encoded glycinamide ribonucleotide transformylase from E. coli (PDB:1kj8, d). A superposition of the molecules from each class (f). The retrieval rate for each binding surface against the GPSS library is shown as an ROC plot in (e). The retrieval rates are calculated using the SurfaceScreen score.
Mentions: ATP is a multifunctional nucleotide associated that has been classified to catalyze 58 different reactions by the Enzyme Commission (EC). In over 300 structural complexes, ATP binding is associated with domains from 45 homologous superfamilies, some sharing less than 8% sequence identity[52]. The nucleotide is quite flexible and adopts a wide range of conformations, some in less than energetically favorable states[52]. To determine the extent that conformational variability exerts on similarity searching, we conducted retrieval experiments with query surfaces binding ATP in diverse conformations: cAMP- dependent kinase (PDB:1atp) protein kinase CK2 from Z. mays (PDB:1a6o)[53], ATP:corrinoid adenosyltransferase from S. typhimurium (PDB:1g5t)[54], PurT-encoded glycinamide ribonucleotide transformylase from E. coli (PDB:1kj8)[55]. The conformations were selected by clustering all ATP molecules by their three-dimensional shape similarity (see Methods) and are shown in Figure 10.

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