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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 CE (Combinatorial Extension) superposition of A. the H3 loop of the complexed 1IFH PDB structure upon the H3 loop of the uncomplexed 1HIL PDB structure. B. the H3 loop of the complexed 2VIR PDB structure upon the H3 loop of the uncomplexed 1GIG PDB structure.
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Figure 6: A CE (Combinatorial Extension) superposition of A. the H3 loop of the complexed 1IFH PDB structure upon the H3 loop of the uncomplexed 1HIL PDB structure. B. the H3 loop of the complexed 2VIR PDB structure upon the H3 loop of the uncomplexed 1GIG PDB structure.

Mentions: A few words should be devoted to the relationship between the intent of the previous X-ray studies and the objectives of the present study. The later X-ray study [6] had focused on the effect of two mutant antigens in inducing structural distortions of the bound complex that could be responsible for the evasion of antibody neutralization. An earlier rigid-body docking study [12] had examined the effect of a number of mutations upon HC19 antibody binding. The present study does not address this issue and has focused solely upon the 2VIR structure; namely, the complex involving the wild type antigenic hemagglutinin "top". The earlier study [8] involved an extensive examination of the structural differences that occur due to antibody binding. Differences in the binding to three different antigenic mimetics of HA1 were examined. It was emphasized that the information obtained was encouraging for attempts to design synthetic vaccines on the basis of X-ray structures of anti-body-peptide complexes [8]. It was also stated that only by comparing the free, unliganded structure with its complexed form is it possible to asses the extent and contribution of conformational changes to the antigen recognition process; a statement supportive of the strategy of the present work. Furthermore, it was stated that, Although many Fab Structures have been determined as complexes, only a few have also been described in their uncomplexed state; a situation which is paralleled to this date since there are, presently, many fewer uncomplexed immunoglobulin structures than complexed structures. Finally, extreme differences in the extent of the conformational adaptations in antibodies as a consequence of antigenic binding had been noted [13], and, a large conformational change observed in the H3 loop between the free and bound form [8] was found. This large conformational change of the H3 CDR loop of the 1IFH structure contrasts significantly with the corresponding change of the H3 CDR loop of the 2VIR structure. This difference is illustrated in figure 6 by a CE (Combinatorial Extension) superposition [14] of the H3 antibody loops of the 2VIR and 1IFH PDB complexed structures, upon their respective H3 loops of the1GIG and 1HIL PDB uncomplexed structures. A similar superposition had been previously performed for the CDR loops of the anti HIV Fab 50.1 [15]. The relatively greater distortion of the H3 loop of 1IFH structure compared with that of 2VIR is consistent with the idea that shape complementarity ...for the smaller, flexible peptides can more easily achieve closer contact with the paratope surface [16]. Such relatively large structural change of the N-terminal heavy chain domain of the1IFH structure upon binding will be shown to require modification of the present procedure to properly represent the observed structural changes. This provides an example of how the substructures of a set of structures may be selected to obtain sets of relatively invariant principal axes to be used for structural comparison.


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 CE (Combinatorial Extension) superposition of A. the H3 loop of the complexed 1IFH PDB structure upon the H3 loop of the uncomplexed 1HIL PDB structure. B. the H3 loop of the complexed 2VIR PDB structure upon the H3 loop of the uncomplexed 1GIG PDB structure.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: A CE (Combinatorial Extension) superposition of A. the H3 loop of the complexed 1IFH PDB structure upon the H3 loop of the uncomplexed 1HIL PDB structure. B. the H3 loop of the complexed 2VIR PDB structure upon the H3 loop of the uncomplexed 1GIG PDB structure.
Mentions: A few words should be devoted to the relationship between the intent of the previous X-ray studies and the objectives of the present study. The later X-ray study [6] had focused on the effect of two mutant antigens in inducing structural distortions of the bound complex that could be responsible for the evasion of antibody neutralization. An earlier rigid-body docking study [12] had examined the effect of a number of mutations upon HC19 antibody binding. The present study does not address this issue and has focused solely upon the 2VIR structure; namely, the complex involving the wild type antigenic hemagglutinin "top". The earlier study [8] involved an extensive examination of the structural differences that occur due to antibody binding. Differences in the binding to three different antigenic mimetics of HA1 were examined. It was emphasized that the information obtained was encouraging for attempts to design synthetic vaccines on the basis of X-ray structures of anti-body-peptide complexes [8]. It was also stated that only by comparing the free, unliganded structure with its complexed form is it possible to asses the extent and contribution of conformational changes to the antigen recognition process; a statement supportive of the strategy of the present work. Furthermore, it was stated that, Although many Fab Structures have been determined as complexes, only a few have also been described in their uncomplexed state; a situation which is paralleled to this date since there are, presently, many fewer uncomplexed immunoglobulin structures than complexed structures. Finally, extreme differences in the extent of the conformational adaptations in antibodies as a consequence of antigenic binding had been noted [13], and, a large conformational change observed in the H3 loop between the free and bound form [8] was found. This large conformational change of the H3 CDR loop of the 1IFH structure contrasts significantly with the corresponding change of the H3 CDR loop of the 2VIR structure. This difference is illustrated in figure 6 by a CE (Combinatorial Extension) superposition [14] of the H3 antibody loops of the 2VIR and 1IFH PDB complexed structures, upon their respective H3 loops of the1GIG and 1HIL PDB uncomplexed structures. A similar superposition had been previously performed for the CDR loops of the anti HIV Fab 50.1 [15]. The relatively greater distortion of the H3 loop of 1IFH structure compared with that of 2VIR is consistent with the idea that shape complementarity ...for the smaller, flexible peptides can more easily achieve closer contact with the paratope surface [16]. Such relatively large structural change of the N-terminal heavy chain domain of the1IFH structure upon binding will be shown to require modification of the present procedure to properly represent the observed structural changes. This provides an example of how the substructures of a set of structures may be selected to obtain sets of relatively invariant principal axes to be used for structural comparison.

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