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Structural deformation upon protein-protein interaction: a structural alphabet approach.

Martin J, Regad L, Lecornet H, Camproux AC - BMC Struct. Biol. (2008)

Bottom Line: Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%).This proportion is even greater in the interface regions (41%).These results could be of help for flexible docking.

View Article: PubMed Central - HTML - PubMed

Affiliation: Equipe de Bioinformatique Génomique et Moléculaire, INSERM UMRS726/Université Denis Diderot Paris 7, F-75005 Paris, France. juliette.martin@jouy.inra.fr

ABSTRACT

Background: In a number of protein-protein complexes, the 3D structures of bound and unbound partners significantly differ, supporting the induced fit hypothesis for protein-protein binding.

Results: In this study, we explore the induced fit modifications on a set of 124 proteins available in both bound and unbound forms, in terms of local structure. The local structure is described thanks to a structural alphabet of 27 structural letters that allows a detailed description of the backbone. Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%). This proportion is even greater in the interface regions (41%). Interface regions preferentially involve coils. Our analysis further reveals that some structural letters in coil are not favored in the interface. We show that certain structural letters in coil are particularly subject to modifications at the interface, and that the severity of structural change also varies. These information are used to derive a structural letter substitution matrix that summarizes the local structural changes observed in our data set. We also illustrate the usefulness of our approach to identify common binding motifs in unrelated proteins.

Conclusion: Our study provides qualitative information about induced fit. These results could be of help for flexible docking.

Show MeSH
Examples of local structural changes induced by protein-protein binding. Proteins are colored according to the rmsddev of the letter substitution unbound/bound form, using same color scheme as in Figure 5: white = local rmsd lower than 0.2Å, gray = local rmsd between 0.2 and 0.5 Å, yellow = local rmsd between 0.5 and 1 Å, green = local rmsd between 1 and 1.5 Å, red = local rmsd greater than 1.5 Å. The superimposition of bound and unbound structures (in magenta), is shown for the modified region. The structural encoding are shown for the interface region that are modified: > u: unbound encoding, > b: bound encoding.
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Figure 7: Examples of local structural changes induced by protein-protein binding. Proteins are colored according to the rmsddev of the letter substitution unbound/bound form, using same color scheme as in Figure 5: white = local rmsd lower than 0.2Å, gray = local rmsd between 0.2 and 0.5 Å, yellow = local rmsd between 0.5 and 1 Å, green = local rmsd between 1 and 1.5 Å, red = local rmsd greater than 1.5 Å. The superimposition of bound and unbound structures (in magenta), is shown for the modified region. The structural encoding are shown for the interface region that are modified: > u: unbound encoding, > b: bound encoding.

Mentions: Figure 7 illustrates some examples of structural letter substitutions induced by protein-protein interaction. These four complexes are taken from the enzyme-substrate class (Figure 7a, b and 7d) and the other class (Figure 7c). In these four examples, drastic local changes (local rmsd greater than 1.5 Å) occur in the interface regions, within loops. We report the structural sequences of the modified regions, in bound and unbound forms. 1RLB, shown in Figure 7a, is a transthyretin/retinol binding complex. The chain A of transtyretin (the receptor) has a Cα rmsd equal to 0.7 Å between bound and unbound forms and 47% of the structural letters are modified. A structural modification of region 98–106 includes 2 substitutions associated to local rmsd greater than 1.5 Å: [H] to [O] and [L] to [Q]. A less severe substitution (local rmsd between 1 and 1.5 Å) occurs from [I] and [D]. 1WQ1, shown in Figure 7b, is a ras GTPase/ras GAP complex. Ras GAP (the ligand) is modified in two distinct regions: in loop 28–39 and loop 58–70. Its global Cα rmsd is 1.1 Å and its percentage of structural letter substitution is 51%. In region 28–39, a run of 7 successive structural letters undergo modifications greater than 0.5 Å, whereas in region 58–70, a run of 8 successive structural letters are strongly modified. Region 58–70 involves letters [J,Q], which are over-modified in interface regions. 1ACB, shown in Figure 7c, is a chymotrypsin/eglin C complex.


Structural deformation upon protein-protein interaction: a structural alphabet approach.

Martin J, Regad L, Lecornet H, Camproux AC - BMC Struct. Biol. (2008)

Examples of local structural changes induced by protein-protein binding. Proteins are colored according to the rmsddev of the letter substitution unbound/bound form, using same color scheme as in Figure 5: white = local rmsd lower than 0.2Å, gray = local rmsd between 0.2 and 0.5 Å, yellow = local rmsd between 0.5 and 1 Å, green = local rmsd between 1 and 1.5 Å, red = local rmsd greater than 1.5 Å. The superimposition of bound and unbound structures (in magenta), is shown for the modified region. The structural encoding are shown for the interface region that are modified: > u: unbound encoding, > b: bound encoding.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2315654&req=5

Figure 7: Examples of local structural changes induced by protein-protein binding. Proteins are colored according to the rmsddev of the letter substitution unbound/bound form, using same color scheme as in Figure 5: white = local rmsd lower than 0.2Å, gray = local rmsd between 0.2 and 0.5 Å, yellow = local rmsd between 0.5 and 1 Å, green = local rmsd between 1 and 1.5 Å, red = local rmsd greater than 1.5 Å. The superimposition of bound and unbound structures (in magenta), is shown for the modified region. The structural encoding are shown for the interface region that are modified: > u: unbound encoding, > b: bound encoding.
Mentions: Figure 7 illustrates some examples of structural letter substitutions induced by protein-protein interaction. These four complexes are taken from the enzyme-substrate class (Figure 7a, b and 7d) and the other class (Figure 7c). In these four examples, drastic local changes (local rmsd greater than 1.5 Å) occur in the interface regions, within loops. We report the structural sequences of the modified regions, in bound and unbound forms. 1RLB, shown in Figure 7a, is a transthyretin/retinol binding complex. The chain A of transtyretin (the receptor) has a Cα rmsd equal to 0.7 Å between bound and unbound forms and 47% of the structural letters are modified. A structural modification of region 98–106 includes 2 substitutions associated to local rmsd greater than 1.5 Å: [H] to [O] and [L] to [Q]. A less severe substitution (local rmsd between 1 and 1.5 Å) occurs from [I] and [D]. 1WQ1, shown in Figure 7b, is a ras GTPase/ras GAP complex. Ras GAP (the ligand) is modified in two distinct regions: in loop 28–39 and loop 58–70. Its global Cα rmsd is 1.1 Å and its percentage of structural letter substitution is 51%. In region 28–39, a run of 7 successive structural letters undergo modifications greater than 0.5 Å, whereas in region 58–70, a run of 8 successive structural letters are strongly modified. Region 58–70 involves letters [J,Q], which are over-modified in interface regions. 1ACB, shown in Figure 7c, is a chymotrypsin/eglin C complex.

Bottom Line: Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%).This proportion is even greater in the interface regions (41%).These results could be of help for flexible docking.

View Article: PubMed Central - HTML - PubMed

Affiliation: Equipe de Bioinformatique Génomique et Moléculaire, INSERM UMRS726/Université Denis Diderot Paris 7, F-75005 Paris, France. juliette.martin@jouy.inra.fr

ABSTRACT

Background: In a number of protein-protein complexes, the 3D structures of bound and unbound partners significantly differ, supporting the induced fit hypothesis for protein-protein binding.

Results: In this study, we explore the induced fit modifications on a set of 124 proteins available in both bound and unbound forms, in terms of local structure. The local structure is described thanks to a structural alphabet of 27 structural letters that allows a detailed description of the backbone. Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%). This proportion is even greater in the interface regions (41%). Interface regions preferentially involve coils. Our analysis further reveals that some structural letters in coil are not favored in the interface. We show that certain structural letters in coil are particularly subject to modifications at the interface, and that the severity of structural change also varies. These information are used to derive a structural letter substitution matrix that summarizes the local structural changes observed in our data set. We also illustrate the usefulness of our approach to identify common binding motifs in unrelated proteins.

Conclusion: Our study provides qualitative information about induced fit. These results could be of help for flexible docking.

Show MeSH