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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.

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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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Unique conformation of p38 MAP kinase creates similar binding surface to c-Abl kinase. The binding surface of inhibitor STI-571 in c-Abl kinase (a, PDB:1opj) shows strong similarity to the binding surface of inhibitor B96 in p38 MAP kinase (b, PDB:1kv2). p38 MAP kinase has DFG motif configuration (stick representation) similar to that seen in c-Abl. SurfaceAlign superposition of the surfaces (c). STI-571 is posed into the p38 MAP binding surface based on the surface alignments (d).
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Figure 15: Unique conformation of p38 MAP kinase creates similar binding surface to c-Abl kinase. The binding surface of inhibitor STI-571 in c-Abl kinase (a, PDB:1opj) shows strong similarity to the binding surface of inhibitor B96 in p38 MAP kinase (b, PDB:1kv2). p38 MAP kinase has DFG motif configuration (stick representation) similar to that seen in c-Abl. SurfaceAlign superposition of the surfaces (c). STI-571 is posed into the p38 MAP binding surface based on the surface alignments (d).

Mentions: The 2-phenylaminopyrimidine-type inhibitor STI-571 (Figure 15a) is an effective inhibitor of c-Abl activity for treatment against CML [64-66]. It has been shown to be specific for tyrosine kinases and also inhibits stem-cell factor receptor kinase c-Kit (PDB:1t46). Results from querying c-Abl (PDB:1opj, Figure 15a) against the GPSS library show cKit is the best scoring non-ABL kinase. This cross reactivity is detected in our cluster (Figure 14b).


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

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

Unique conformation of p38 MAP kinase creates similar binding surface to c-Abl kinase. The binding surface of inhibitor STI-571 in c-Abl kinase (a, PDB:1opj) shows strong similarity to the binding surface of inhibitor B96 in p38 MAP kinase (b, PDB:1kv2). p38 MAP kinase has DFG motif configuration (stick representation) similar to that seen in c-Abl. SurfaceAlign superposition of the surfaces (c). STI-571 is posed into the p38 MAP binding surface based on the surface alignments (d).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 15: Unique conformation of p38 MAP kinase creates similar binding surface to c-Abl kinase. The binding surface of inhibitor STI-571 in c-Abl kinase (a, PDB:1opj) shows strong similarity to the binding surface of inhibitor B96 in p38 MAP kinase (b, PDB:1kv2). p38 MAP kinase has DFG motif configuration (stick representation) similar to that seen in c-Abl. SurfaceAlign superposition of the surfaces (c). STI-571 is posed into the p38 MAP binding surface based on the surface alignments (d).
Mentions: The 2-phenylaminopyrimidine-type inhibitor STI-571 (Figure 15a) is an effective inhibitor of c-Abl activity for treatment against CML [64-66]. It has been shown to be specific for tyrosine kinases and also inhibits stem-cell factor receptor kinase c-Kit (PDB:1t46). Results from querying c-Abl (PDB:1opj, Figure 15a) against the GPSS library show cKit is the best scoring non-ABL kinase. This cross reactivity is detected in our cluster (Figure 14b).

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