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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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Identification of a convergent heme binding surfaces from surface similarity. Despite lacking sequence or structural homology to the heme-monooxygenase family, IsdG from S. aureus (a, yellow) contains a conserved surface allowing it to perform heme-monooxygenase activity. When compared to the heme binding surface from heme oxygenase (HmuO) from C. diphtheria (b, green), 19 residues are conserved (c) with similar global shape characteristics (d). The superposition of the conserved residues is shown for the best scoring cRMSD (e) and oRMSD (g) alignments. The alignments are colored by residue type (IsgG large radius, HmuO small radius) in (fh). The superposition of the surfaces resulting in the maximum volume overlap (i, red) is shown with bound heme from HmuO (j).
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Figure 8: Identification of a convergent heme binding surfaces from surface similarity. Despite lacking sequence or structural homology to the heme-monooxygenase family, IsdG from S. aureus (a, yellow) contains a conserved surface allowing it to perform heme-monooxygenase activity. When compared to the heme binding surface from heme oxygenase (HmuO) from C. diphtheria (b, green), 19 residues are conserved (c) with similar global shape characteristics (d). The superposition of the conserved residues is shown for the best scoring cRMSD (e) and oRMSD (g) alignments. The alignments are colored by residue type (IsgG large radius, HmuO small radius) in (fh). The superposition of the surfaces resulting in the maximum volume overlap (i, red) is shown with bound heme from HmuO (j).

Mentions: The structure of IsdG has a prominent pocket formed between the α-helices and beta sheets (Figure 8a). This is the largest surface pocket identified by the CASTp webserver[50]. Querying this surface against the GPSS library reveals a striking similarity to the heme binding pocket in heme oxygenase (HmuO) from C. diphtheriae (PDB:1iw0, Figure 8b). The SSS distributions have distance of 0.06 (Figure 8d). There are 19 conserved residues between the surfaces that come from diverse regions of the primary sequence (Figure 8c). The surfaces align with cRMSD P-value of 9.84 × 10-3 (Figure 8ef) and oRMSD P-value of 5.32 × 10-4 (Figure 8gh). Superposition of the surfaces results in gSVOT of 0.78, lSVOT 0.84, and rSVOT of 0.93 (Figure 8i). The gSVOT overlap is highlighted in Figure 8j. The SurfaceScreen score for the comparison is 1.98, which ranked fourth overall against the search library.


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

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

Identification of a convergent heme binding surfaces from surface similarity. Despite lacking sequence or structural homology to the heme-monooxygenase family, IsdG from S. aureus (a, yellow) contains a conserved surface allowing it to perform heme-monooxygenase activity. When compared to the heme binding surface from heme oxygenase (HmuO) from C. diphtheria (b, green), 19 residues are conserved (c) with similar global shape characteristics (d). The superposition of the conserved residues is shown for the best scoring cRMSD (e) and oRMSD (g) alignments. The alignments are colored by residue type (IsgG large radius, HmuO small radius) in (fh). The superposition of the surfaces resulting in the maximum volume overlap (i, red) is shown with bound heme from HmuO (j).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Identification of a convergent heme binding surfaces from surface similarity. Despite lacking sequence or structural homology to the heme-monooxygenase family, IsdG from S. aureus (a, yellow) contains a conserved surface allowing it to perform heme-monooxygenase activity. When compared to the heme binding surface from heme oxygenase (HmuO) from C. diphtheria (b, green), 19 residues are conserved (c) with similar global shape characteristics (d). The superposition of the conserved residues is shown for the best scoring cRMSD (e) and oRMSD (g) alignments. The alignments are colored by residue type (IsgG large radius, HmuO small radius) in (fh). The superposition of the surfaces resulting in the maximum volume overlap (i, red) is shown with bound heme from HmuO (j).
Mentions: The structure of IsdG has a prominent pocket formed between the α-helices and beta sheets (Figure 8a). This is the largest surface pocket identified by the CASTp webserver[50]. Querying this surface against the GPSS library reveals a striking similarity to the heme binding pocket in heme oxygenase (HmuO) from C. diphtheriae (PDB:1iw0, Figure 8b). The SSS distributions have distance of 0.06 (Figure 8d). There are 19 conserved residues between the surfaces that come from diverse regions of the primary sequence (Figure 8c). The surfaces align with cRMSD P-value of 9.84 × 10-3 (Figure 8ef) and oRMSD P-value of 5.32 × 10-4 (Figure 8gh). Superposition of the surfaces results in gSVOT of 0.78, lSVOT 0.84, and rSVOT of 0.93 (Figure 8i). The gSVOT overlap is highlighted in Figure 8j. The SurfaceScreen score for the comparison is 1.98, which ranked fourth overall against the search library.

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
Related in: MedlinePlus