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Using molecular principal axes for structural comparison: determining the tertiary changes of a FAB antibody domain induced by antigenic binding.

Silverman BD - BMC Struct. Biol. (2007)

Bottom Line: Comparison of different protein x-ray structures has previously been made in a number of different ways; for example, by visual examination, by differences in the locations of secondary structures, by explicit superposition of structural elements, e.g. alpha-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared.Second, changes in the ellipsoidal distances with respect to the non-interacting structure provide a direct measure of the spatial displacements of the residue centroids, towards either the interior or exterior of the domain.With use of x-ray data from the protein data bank (PDB), these two metrics are shown to highlight, in a manner different from before, the structural changes that are induced in the overall domains as well as in the H3 loops of the complementarity-determining regions (CDR) upon FAB antibody binding to a truncated and to a synthetic hemagglutinin viral antigenic target.

View Article: PubMed Central - HTML - PubMed

Affiliation: IBM Thomas J, Watson Research Center P, O, Box 218, Yorktown Heights, NY 10598, USA. silverma@us.ibm.com

ABSTRACT

Background: Comparison of different protein x-ray structures has previously been made in a number of different ways; for example, by visual examination, by differences in the locations of secondary structures, by explicit superposition of structural elements, e.g. alpha-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared.

Results: A new approach is applied to determine the structural changes that an antibody protein domain experiences upon its interaction with an antigenic target. These changes are determined with the use of two different, however comparable, sets of principal axes that are obtained by diagonalizing the second-order tensors that yield the moments-of-geometry as well as an ellipsoidal characterization of domain shape, prior to and after interaction. Determination of these sets of axes for structural comparison requires no internal symmetry features of the domains, depending solely upon their representation in three-dimensional space. This representation may involve atomic, Calpha, or residue centroid coordinates. The present analysis utilizes residue centroids. When the structural changes are minimal, the principal axes of the domains, prior to and after interaction, are essentially comparable and consequently may be used for structural comparison. When the differences of the axes cannot be neglected, but are nevertheless slight, a smaller relatively invariant substructure of the domains may be utilized for comparison. The procedure yields two distance metrics for structural comparison. First, the displacements of the residue centroids due to antigenic binding, referenced to the ellipsoidal principal axes, are noted. Second, changes in the ellipsoidal distances with respect to the non-interacting structure provide a direct measure of the spatial displacements of the residue centroids, towards either the interior or exterior of the domain.

Conclusion: With use of x-ray data from the protein data bank (PDB), these two metrics are shown to highlight, in a manner different from before, the structural changes that are induced in the overall domains as well as in the H3 loops of the complementarity-determining regions (CDR) upon FAB antibody binding to a truncated and to a synthetic hemagglutinin viral antigenic target.

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A. The Displacements of the amino acid centroids from their locations in the unliganded domain of the light chain (PDB file, 1GIG) to their locations in the complexed domain of the light chain (PDB file, 2VIR). B. The Displacements described in A, shown on an expanded scale about the amino acid residues of greatest Displacement. C. The differences in the ellipsoidal distances (Differential Ellipsoidal Distances) of the amino acid centroids of the light chain domain of the complex (PDB, 2VIR) from their values in the uncomplexed light chain domain (PDB, 1GIG). D. The differences described in C, shown on an expanded scale about the amino acid residues showing the greatest differences.
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Figure 5: A. The Displacements of the amino acid centroids from their locations in the unliganded domain of the light chain (PDB file, 1GIG) to their locations in the complexed domain of the light chain (PDB file, 2VIR). B. The Displacements described in A, shown on an expanded scale about the amino acid residues of greatest Displacement. C. The differences in the ellipsoidal distances (Differential Ellipsoidal Distances) of the amino acid centroids of the light chain domain of the complex (PDB, 2VIR) from their values in the uncomplexed light chain domain (PDB, 1GIG). D. The differences described in C, shown on an expanded scale about the amino acid residues showing the greatest differences.

Mentions: Figure 5 shows the displacements and the differential ellipsoidal distances obtained for the amino acids of the light chain. The ordinate scales of figures 5A and 5C have been chosen with the same extent as those of figures 1A and 1C. The smaller displacements and differences of the light chain compared with those of the heavy chain highlight the weaker binding of the antigenic epitope to the light compared with the heavy chain. Examination of the bound structure shows the antigenic epitope to be at a much greater distance from the light chain than its distance from the heavy chain. Aside from the amino acids bracketed by the dashed lines, the displacements and differences in ellipsoidal distances are small; less than 1 Angstrom on average. The bracketed amino acids include TYR94 to ASN96. A number of close distances between the heavy atoms of the amino acid ASN96 of this group and those of SER159 of the "HA-top" are apparently responsible for the interactions that contribute to the enhanced values of the displacements of this group of residues. Furthermore, the lack of correspondence between the magnitudes of the displacements and differential ellipsoidal distances for all of the residues, and in particular for the residues TYR94 and SER95 of this set, is observed and this once again emphasizes the complementary nature of the information provided by these two different spatial metrics.


Using molecular principal axes for structural comparison: determining the tertiary changes of a FAB antibody domain induced by antigenic binding.

Silverman BD - BMC Struct. Biol. (2007)

A. The Displacements of the amino acid centroids from their locations in the unliganded domain of the light chain (PDB file, 1GIG) to their locations in the complexed domain of the light chain (PDB file, 2VIR). B. The Displacements described in A, shown on an expanded scale about the amino acid residues of greatest Displacement. C. The differences in the ellipsoidal distances (Differential Ellipsoidal Distances) of the amino acid centroids of the light chain domain of the complex (PDB, 2VIR) from their values in the uncomplexed light chain domain (PDB, 1GIG). D. The differences described in C, shown on an expanded scale about the amino acid residues showing the greatest differences.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2238760&req=5

Figure 5: A. The Displacements of the amino acid centroids from their locations in the unliganded domain of the light chain (PDB file, 1GIG) to their locations in the complexed domain of the light chain (PDB file, 2VIR). B. The Displacements described in A, shown on an expanded scale about the amino acid residues of greatest Displacement. C. The differences in the ellipsoidal distances (Differential Ellipsoidal Distances) of the amino acid centroids of the light chain domain of the complex (PDB, 2VIR) from their values in the uncomplexed light chain domain (PDB, 1GIG). D. The differences described in C, shown on an expanded scale about the amino acid residues showing the greatest differences.
Mentions: Figure 5 shows the displacements and the differential ellipsoidal distances obtained for the amino acids of the light chain. The ordinate scales of figures 5A and 5C have been chosen with the same extent as those of figures 1A and 1C. The smaller displacements and differences of the light chain compared with those of the heavy chain highlight the weaker binding of the antigenic epitope to the light compared with the heavy chain. Examination of the bound structure shows the antigenic epitope to be at a much greater distance from the light chain than its distance from the heavy chain. Aside from the amino acids bracketed by the dashed lines, the displacements and differences in ellipsoidal distances are small; less than 1 Angstrom on average. The bracketed amino acids include TYR94 to ASN96. A number of close distances between the heavy atoms of the amino acid ASN96 of this group and those of SER159 of the "HA-top" are apparently responsible for the interactions that contribute to the enhanced values of the displacements of this group of residues. Furthermore, the lack of correspondence between the magnitudes of the displacements and differential ellipsoidal distances for all of the residues, and in particular for the residues TYR94 and SER95 of this set, is observed and this once again emphasizes the complementary nature of the information provided by these two different spatial metrics.

Bottom Line: Comparison of different protein x-ray structures has previously been made in a number of different ways; for example, by visual examination, by differences in the locations of secondary structures, by explicit superposition of structural elements, e.g. alpha-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared.Second, changes in the ellipsoidal distances with respect to the non-interacting structure provide a direct measure of the spatial displacements of the residue centroids, towards either the interior or exterior of the domain.With use of x-ray data from the protein data bank (PDB), these two metrics are shown to highlight, in a manner different from before, the structural changes that are induced in the overall domains as well as in the H3 loops of the complementarity-determining regions (CDR) upon FAB antibody binding to a truncated and to a synthetic hemagglutinin viral antigenic target.

View Article: PubMed Central - HTML - PubMed

Affiliation: IBM Thomas J, Watson Research Center P, O, Box 218, Yorktown Heights, NY 10598, USA. silverma@us.ibm.com

ABSTRACT

Background: Comparison of different protein x-ray structures has previously been made in a number of different ways; for example, by visual examination, by differences in the locations of secondary structures, by explicit superposition of structural elements, e.g. alpha-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared.

Results: A new approach is applied to determine the structural changes that an antibody protein domain experiences upon its interaction with an antigenic target. These changes are determined with the use of two different, however comparable, sets of principal axes that are obtained by diagonalizing the second-order tensors that yield the moments-of-geometry as well as an ellipsoidal characterization of domain shape, prior to and after interaction. Determination of these sets of axes for structural comparison requires no internal symmetry features of the domains, depending solely upon their representation in three-dimensional space. This representation may involve atomic, Calpha, or residue centroid coordinates. The present analysis utilizes residue centroids. When the structural changes are minimal, the principal axes of the domains, prior to and after interaction, are essentially comparable and consequently may be used for structural comparison. When the differences of the axes cannot be neglected, but are nevertheless slight, a smaller relatively invariant substructure of the domains may be utilized for comparison. The procedure yields two distance metrics for structural comparison. First, the displacements of the residue centroids due to antigenic binding, referenced to the ellipsoidal principal axes, are noted. Second, changes in the ellipsoidal distances with respect to the non-interacting structure provide a direct measure of the spatial displacements of the residue centroids, towards either the interior or exterior of the domain.

Conclusion: With use of x-ray data from the protein data bank (PDB), these two metrics are shown to highlight, in a manner different from before, the structural changes that are induced in the overall domains as well as in the H3 loops of the complementarity-determining regions (CDR) upon FAB antibody binding to a truncated and to a synthetic hemagglutinin viral antigenic target.

Show MeSH