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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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Mapping ATP binding surface cluster membership and ATP conformation class. Observed frequencies for hydrolases (a), ligases (b), and transferases (c) are shown. Surface cluster numbers correspond to Figure 11(b). ATP conformation class labels correspond to Figure 9. The sums for each row and column are shown on the edges of each plot.
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Figure 13: Mapping ATP binding surface cluster membership and ATP conformation class. Observed frequencies for hydrolases (a), ligases (b), and transferases (c) are shown. Surface cluster numbers correspond to Figure 11(b). ATP conformation class labels correspond to Figure 9. The sums for each row and column are shown on the edges of each plot.

Mentions: The cluster results show that there is minimal functional exclusivity between binding surfaces and ATP conformation. The same enzymatic functions can be accomplished using a variety of binding surfaces and, within each surface, multiple ligand conformations can be bound. In the most well represented functional families, hyrdolases, ligases, and transferases, we observe different degrees of binding mode conservation. A breakdown of surface clustering and ligand conformations is shown as a balloon plot in Figure 13. Hydrolases have two conformation preferences and favor, deep, encapsulating binding surfaces. Bent form ATP is disfavored in hydrolases. Ligases are the most conserved, heavily favoring the bent form of ATP that requires a wide-mouth surface shape. Transferases are the most adept of the ATP binding proteins, sampling the most surface/conformation combinations. They do not discriminate between ATP conformations but have a preference for encapsulating binding sites. Several combinations occur with higher frequencies, including an exclusive combination (4-◆), which is the most observed in this family.


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

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

Mapping ATP binding surface cluster membership and ATP conformation class. Observed frequencies for hydrolases (a), ligases (b), and transferases (c) are shown. Surface cluster numbers correspond to Figure 11(b). ATP conformation class labels correspond to Figure 9. The sums for each row and column are shown on the edges of each plot.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 13: Mapping ATP binding surface cluster membership and ATP conformation class. Observed frequencies for hydrolases (a), ligases (b), and transferases (c) are shown. Surface cluster numbers correspond to Figure 11(b). ATP conformation class labels correspond to Figure 9. The sums for each row and column are shown on the edges of each plot.
Mentions: The cluster results show that there is minimal functional exclusivity between binding surfaces and ATP conformation. The same enzymatic functions can be accomplished using a variety of binding surfaces and, within each surface, multiple ligand conformations can be bound. In the most well represented functional families, hyrdolases, ligases, and transferases, we observe different degrees of binding mode conservation. A breakdown of surface clustering and ligand conformations is shown as a balloon plot in Figure 13. Hydrolases have two conformation preferences and favor, deep, encapsulating binding surfaces. Bent form ATP is disfavored in hydrolases. Ligases are the most conserved, heavily favoring the bent form of ATP that requires a wide-mouth surface shape. Transferases are the most adept of the ATP binding proteins, sampling the most surface/conformation combinations. They do not discriminate between ATP conformations but have a preference for encapsulating binding sites. Several combinations occur with higher frequencies, including an exclusive combination (4-◆), which is the most observed in this family.

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