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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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The orientation of the heavy chain residues TYR102 and PHE105 in the uncomplexed structure (1GIG) (figure 3A) and in the complexed structure (2VIR) (figure (3B), respectively, with respect to the bulk of the heavy chain (off and to the right of the figure).
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Figure 3: The orientation of the heavy chain residues TYR102 and PHE105 in the uncomplexed structure (1GIG) (figure 3A) and in the complexed structure (2VIR) (figure (3B), respectively, with respect to the bulk of the heavy chain (off and to the right of the figure).

Mentions: Calculations have been performed utilizing the x-ray structure of a free HC19 FAB [7; pdb id 1GIG] and the structure of the HC19 FAB in complex with the membrane distal domain of X31 hemagglutinin ('HA-top') [6; pdb id 2VIR]. Figures 1A and 1C show the displacements and differences in ellipsoidal distances in Angstroms of the amino acid centroids of the N-terminal FAB heavy chain domain of the complex, from their locations in the free or unliganded antibody domain. First, one notes, that aside from the regions of amino acids that are bracketed by the dashed lines or specifically labeled, the displacements and differences are small, mainly less than 1 Angstrom, confirming that a major portion of the overall antibody structure, before and after binding is comparable. The bracketed region spans residues PHE99 to TYR107. This region, the region undergoing the most extensive structural modification of the antibody upon binding to the truncated "HA top" involves the tip of the H3 CDR (complementarity-determining region). It is highlighted in white in figure 2. Figures 1B and 1D, which are expanded views of the bracketed regions, accentuate the complementarity of the information provided by the two different distance metrics. Note that the amino acid with the greatest displacement, TYR102 in figure 1B, shows a difference in ellipsoidal distance in figure 1D that is approximately equal to zero; whereas PHE105, which has a displacement less than TYR102 exhibits the largest value of differential ellipsoidal distance. Figure 3 illustrates the reason for this difference. Comparison of figure 3A with figure 3b shows that the structural modification of the H3 loop upon binding involves the swapping of the location of TYR102, behind the loop shown in the unliganded structure of figure 3A, to a location in front of the loop in the liganded complex shown in figure 3B. While this involves a relatively large displacement from its position in the unliganded structure, its distance from the interior of the heavy chain domain (to the right in the figures) is relatively unchanged. This contrasts with the rotation of the PHE105 six-membered ring which clearly places its residue centroid upon complexation at a greater distance from the interior of the heavy chain domain.


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)

The orientation of the heavy chain residues TYR102 and PHE105 in the uncomplexed structure (1GIG) (figure 3A) and in the complexed structure (2VIR) (figure (3B), respectively, with respect to the bulk of the heavy chain (off and to the right of the figure).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2238760&req=5

Figure 3: The orientation of the heavy chain residues TYR102 and PHE105 in the uncomplexed structure (1GIG) (figure 3A) and in the complexed structure (2VIR) (figure (3B), respectively, with respect to the bulk of the heavy chain (off and to the right of the figure).
Mentions: Calculations have been performed utilizing the x-ray structure of a free HC19 FAB [7; pdb id 1GIG] and the structure of the HC19 FAB in complex with the membrane distal domain of X31 hemagglutinin ('HA-top') [6; pdb id 2VIR]. Figures 1A and 1C show the displacements and differences in ellipsoidal distances in Angstroms of the amino acid centroids of the N-terminal FAB heavy chain domain of the complex, from their locations in the free or unliganded antibody domain. First, one notes, that aside from the regions of amino acids that are bracketed by the dashed lines or specifically labeled, the displacements and differences are small, mainly less than 1 Angstrom, confirming that a major portion of the overall antibody structure, before and after binding is comparable. The bracketed region spans residues PHE99 to TYR107. This region, the region undergoing the most extensive structural modification of the antibody upon binding to the truncated "HA top" involves the tip of the H3 CDR (complementarity-determining region). It is highlighted in white in figure 2. Figures 1B and 1D, which are expanded views of the bracketed regions, accentuate the complementarity of the information provided by the two different distance metrics. Note that the amino acid with the greatest displacement, TYR102 in figure 1B, shows a difference in ellipsoidal distance in figure 1D that is approximately equal to zero; whereas PHE105, which has a displacement less than TYR102 exhibits the largest value of differential ellipsoidal distance. Figure 3 illustrates the reason for this difference. Comparison of figure 3A with figure 3b shows that the structural modification of the H3 loop upon binding involves the swapping of the location of TYR102, behind the loop shown in the unliganded structure of figure 3A, to a location in front of the loop in the liganded complex shown in figure 3B. While this involves a relatively large displacement from its position in the unliganded structure, its distance from the interior of the heavy chain domain (to the right in the figures) is relatively unchanged. This contrasts with the rotation of the PHE105 six-membered ring which clearly places its residue centroid upon complexation at a greater distance from the interior of the heavy chain domain.

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