Binding induced conformational changes of proteins correlate with their intrinsic fluctuations: a case study of antibodies

Keskin, Özlem

doi:10.1186/1472-6807-7-31

Cited by 103 publications

(89 citation statements)

References 46 publications

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“…What is the explanation for a preexisting conformational equilibrium in E1ec? One school of thought suggests that conformational equilibria allow proteins to adopt new conformations, which in turn help them to bind distinct ligands without undergoing evolutionary changes (20). Manipulation of conformational equilibrium was successfully used to ''tune'' ligandbinding affinities (21).…”

Section: Discussionmentioning

confidence: 99%

Efficient coupling of catalysis and dynamics in the E1 component of Escherichia coli pyruvate dehydrogenase multienzyme complex

Kale

Ulas

Song

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Thermodynamic studies revealed that these motions may promote covalent addition of substrate to the enzyme-bound thiamin diphosphate by reducing the free energy of activation. Furthermore, the global dynamics of E1 presumably regulate and streamline the catalytic steps of the overall complex by inducing an entirely entropic (nonmechanical) negative cooperativity with respect to substrate binding at higher temperatures. Our results are consistent with, and reinforce the hypothesis of, coupling of catalysis and regulation with enzyme dynamics and suggest the mechanism by which it is achieved in a key branchpoint enzyme in sugar metabolism.coupling of dynamics to catalysis ͉ EPR ͉ mobile loop dynamics ͉ NMR ͉ pyruvate dehydrogenase T he pyruvate dehydrogenase multienzyme complex (PDHc) is an exquisite machine that catalyzes the oxidative decarboxylation of pyruvate to acetyl CoA (1).In Escherichia coli, the PDHc is composed of multiple copies of three components: E1ec, E2ec, and E3ec, which consecutively catalyze part(s) of the above overall reaction. E1ec is a thiamin diphosphate (ThDP)-dependent ␣ 2 homodimer with mass 198,948 Da and catalyzes the reactions shown in supporting information (SI) Scheme I. The crystal structure of E1ec complexed with ThDP revealed two disordered regions near the active site with no discernible electron density (2), spanning residues 401-413 (inner loop) and 541-557 (outer loop), which become ordered in the presence of C2␣-phosphonolactylThDP (PLThDP), a stable analogue of the first ThDP-bound predecarboxylation covalent intermediate C2␣-lactylThDP (LThDP) (3) (Fig. 1). The enzyme could also catalyze very efficiently the formation of PLThDP from methyl acetylphosphonate (MAP), an excellent electrostatic analogue of pyruvate (SI Scheme II).The dynamic behavior of these active center loops in E1ec is critical for catalytic functions starting from a predecarboxylation event and culminating in transfer of the acetyl moiety to the E2ec component (i.e., intercomponent communication; ref. 4).The disorder-order transformation in E1ec modulated by the interaction of H407 with PLThDP acts as a ''feed-forward'' switch by preparing the active site for the next step, receiving the lipoamide group of the E2ec component (3). These observations suggested that in E1ec, the dynamics of active-center loops may be correlated to substrate turnover. Correlated biological processes of considerable interest, such as ligand binding, catalysis, and conformational transitions, occur on time scales ranging from picoseconds to days, and the conformational transition is often coupled to ligand binding and catalysis (5-7). The relationship between the time scale of such motions and their specific roles in catalysis is an important current issue in enzymology.Author contributions: S.K., G.W.B., W.F., and F.J. designed research; S.K., G.U., and J.S. performed research; S.K., G.U., G.W.B., and F.J. analyzed data; and S.K., G.W.B., and F.J. wrote the paper.The authors declare no conflict of interest.This article is a ...

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Section: Discussionmentioning

confidence: 99%

Efficient coupling of catalysis and dynamics in the E1 component of Escherichia coli pyruvate dehydrogenase multienzyme complex

Kale

Ulas

Song

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Most importantly, it has been shown that a few lowest frequency modes (or their linear combinations) of unbound conformations obtained by ENMs can capture the conformational change upon binding. [42][43][44] Recently, Dobbins et al 19 applied ENM to a set of proteins from docking benchmark and found that the modes with certain characteristic frequencies can provide guidelines to predict the conformational change on protein-protein docking.…”

Section: Introductionmentioning

confidence: 99%

A flexible docking scheme to explore the binding selectivity of PDZ domains

Gerek

Ozkan

2010

Protein Science

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Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å . We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

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“…Experimental and structural studies suggest that Abs are no different, showing some flexibility upon Ag binding (4). This flexibility was suggested to be essential to their ability to bind multiple Ags (3). However, although the existence of conformational changes in the Ag binding site has been widely recognized, their role in the adaptive immune system has not been structurally elucidated.…”

mentioning

confidence: 99%

“…T he inherent flexibility of proteins is essential for their function, allowing them to adopt new conformations and, in turn, bind to distinct ligands (1)(2)(3). Experimental and structural studies suggest that Abs are no different, showing some flexibility upon Ag binding (4).…”

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confidence: 99%

A Systematic Comparison of Free and Bound Antibodies Reveals Binding-Related Conformational Changes

Sela-Culang

Alon

Ofran

2012

The Journal of Immunology

106

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To study structural changes that occur in Abs upon Ag binding, we systematically compared free and bound structures of all 141 crystal structures of the 49 Abs that were solved in these two forms. We found that many structural changes occur far from the Ag binding site. Some of them may constitute a mechanism for the recently suggested allosteric effects in Abs. Within the binding site itself, CDR-H3 is the only element that shows significant binding-related conformational changes; however, this occurs in only one third of the Abs. Beyond the binding site, Ag binding is associated with changes in the relative orientation of the H and L chains in both the variable and constant domains. An even larger change occurs in the elbow angle between the variable and the constant domains, and it is significantly larger for binding of big Ags than for binding of small ones. The most consistent and substantial conformational changes occur in a loop in the H chain constant domain. This loop is implicated in the interaction between the H and L chains, is often intrinsically disordered, and is involved in complement binding. Hence, we suggest that it may have a role in Ab function. These findings provide structural insight into the recently proposed allosteric effects in Abs.

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Binding induced conformational changes of proteins correlate with their intrinsic fluctuations: a case study of antibodies

Cited by 103 publications

References 46 publications

Efficient coupling of catalysis and dynamics in the E1 component of Escherichia coli pyruvate dehydrogenase multienzyme complex

Efficient coupling of catalysis and dynamics in the E1 component of Escherichia coli pyruvate dehydrogenase multienzyme complex

A flexible docking scheme to explore the binding selectivity of PDZ domains

A Systematic Comparison of Free and Bound Antibodies Reveals Binding-Related Conformational Changes

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