Ligand-dependent Dynamics and Intramolecular Signaling in a PDZ Domain

Fuentes, Ernesto J.; Der, Channing J.; Lee, Andrew L.

doi:10.1016/j.jmb.2003.11.010

Cited by 221 publications

(481 citation statements)

References 60 publications

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“…Three different and well-studied PDZ domains were included in the study, SAP97 PDZ2, PTP-BL PDZ2 and PSD-95 PDZ3. For each of these PDZ domains, we selected a wild-type peptide, based on previous work 32, [34][35][36][37][38] (see legend to Fig. 2 for wild-type and mutant peptides).…”

Section: Resultsmentioning

confidence: 99%

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

et al. 2011

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Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. We have here used short peptides as a model system for intrinsically disordered proteins. Linear free-energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the ratelimiting barrier for binding, in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions.The data do not support the recent notion that the affinities of intrinsically disordered proteins towards their targets are generally governed by their association rate constants.Instead, we observe the opposite for peptide-PDZ interactions, namely that changes in K d correlate with changes in k off .3

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Section: Resultsmentioning

confidence: 99%

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

et al. 2011

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“…It has however been argued that the PDZ2 domain studied here does posses allosteric properties, even when looked at it as an isolated system (see Ref. 11 ). That is, a PDZ domain in a multi-domain protein must still "communicate" somehow with the other domain, to which it is linked and which carries an active site.…”

Section: Characterization Of the Conformational Rearrangementmentioning

confidence: 91%

“…A well-studied example for systems showing ligand-induced allostery are modular domains for protein-protein interactions denoted as PSD95/Discs large/ZO-1 (PDZ) domains. [11][12][13][14][15][16][17][18][19][20] These domains occur in a set of proteins typically associated with cell junctions and mediate the clustering of membrane ion channels by binding to their C-termini. [15][16][17] PDZ domains share a common fold which consists of two α-helices and six β -strands, with the second α-helix and the second β -strand forming the canonical binding groove ( Figure Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20] An example is the PDZ2 domain of human tyrosine phosphatase 1E, a protein involved in the regulation of multiple receptor-coupled signal transduction pathways including programmed cell death. 11 Structural models of the PDZ2 domain based on experimental data suggest that the binding groove opens upon binding. That is, the C α -distance between residues 21 and 76 (green line in Figure Figure 1) increases by 0.08 nm in crystals.…”

Section: Introductionmentioning

confidence: 99%

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Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

et al. 2014

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A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligandbound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and the trans state of the photoswitch, in explicit water. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes, that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein. October 9, 2014 * To whom correspondence should be addressed 1 Abstract A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligandbound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and the trans state of the photoswitch, in explicit water. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes, that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein.

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“…By clustering the binding induced fluctuation profiles of a diverse set of PDZ domains, we showed that ENM predicted normal modes not only can identify the structural regions and types of correlated fluctuations critical for binding of Class I and Class II peptides but also predicts binding selectivity of PDZs. 49 The challenge of PDZ domain (i.e., the reasons behind their selectivity and promiscuity) and their link to many different diseases has led to a number of important experimental 50,51 and computational 49,[52][53][54][55][56][57][58] studies. Niv and Weinstein also developed a flexible docking scheme (called PDZDocScheme), 56 which is based on simulated annealing molecular dynamics with the soft core potential or flexible binding site side chains, followed by rotamer optimization.…”

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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Ligand-dependent Dynamics and Intramolecular Signaling in a PDZ Domain

Cited by 221 publications

References 60 publications

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

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

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