Crystal Structures of the Human p56lckSH2 Domain in Complex with Two Short Phosphotyrosyl Peptides at 1.0 Å and 1.8 Å Resolution

Tong, Liang; Warren, Thomas C.; King, Josephine; Betageri, Raj; Rose, Janice; Jakes, Scott

doi:10.1006/jmbi.1996.0112

Cited by 101 publications

(112 citation statements)

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“…SH2 domains are highly conserved noncatalytic proteins of Ϸ100-aa residues, which can bind phosphotyrosine-containing polypeptide sequences with high affinity and specificity. They are found in a wide variety of intracellular signal transduction pathways involving tyrosine kinases (18)(19)(20)(21)(22), and inappropriate cellular signaling caused by malfunctions of SH2-mediated process has been linked to many pathologic conditions (e.g., cancer, autoimmune diseases, asthma, allergies, etc.). SH2 domains are highly selective toward the sequence phosphotyrosine-Glu-Glu-Ile (pYEEI) (23), with dissociation constants ranging from micromolar to nanomolar ranges (19,24; for a review, see ref.…”

mentioning

confidence: 99%

Calculation of absolute protein–ligand binding free energy from computer simulations

Woo

Roux²

2005

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

622

896

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A general methodology for calculating the equilibrium binding constant of a flexible ligand to a protein receptor is formulated on the basis of potentials of mean force. The overall process is decomposed into several stages that can be computed separately: the free ligand in the bulk is first restrained into the conformation it adopts in the bound state, position, and orientation by applying biasing potentials, then it is translated into the binding site, where it is released completely. The conformational restraining potential is based on the root-mean-square deviation of the peptide coordinates relative to its average conformation in the bound complex. Free energy contributions from each stage are calculated by means of free energy perturbation potential of mean force techniques by using appropriate order parameters. The present approach avoids the need to decouple the ligand from its surrounding (bulk solvent and receptor protein) as is traditionally performed in the doubledecoupling scheme. It is believed that the present formulation will be particularly useful when the solvation free energy of the ligand is very large. As an application, the equilibrium binding constant of the phosphotyrosine peptide pYEEI to the Src homology 2 domain of human Lck has been calculated. The results are in good agreement with experimental values. Approaches at different levels of complexity and sophistication have been used to calculate binding free energies in complex biomolecular systems. Screening of large molecular databases of compounds to identify potential lead drug molecules typically relies on very simplified scoring schemes to achieve the needed efficiency (6). The binding free energy may be estimated on the basis of a continuum solvent approximation assuming quadratic fluctuations around a unique configuration (7,8). The Molecular Mechanics͞ Poisson-Boltzmann (PB) and Surface Area (MM͞PB-SA) method is a popular approach that relies on a mixed scheme combining configurations sampled from molecular dynamics (MD) simulations with explicit solvent, together with free energy estimators based on an implicit continuum solvent model (9). MM͞PB-SA shares some similarities with the linear interaction energy method, which also uses averages calculated from explicit solvent simulations within a linear response framework (10). Despite their usefulness, such approximate schemes can be limited, and how to improve the results is unclear because they do not offer a rigorous route to compute the equilibrium binding constant.In principle, treatments based on MD free energy perturbation (FEP) simulations with explicit solvent molecules offer the most powerful and promising approach to estimate the binding free energies of ligands to macromolecules (11). Nonetheless, although previous studies have provided many of the fundamental elements necessary for the calculation of binding free energy by means of MD (12-17), the computations so far have been limited mostly to fairly small and rigid ligands [e.g., rare gas atom (12, 15), water (14)...

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mentioning

confidence: 99%

Calculation of absolute protein–ligand binding free energy from computer simulations

Woo

Roux²

2005

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

622

896

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“…These structures (e.g. for Lck (35,40) and Src (39)) show that the peptide specificity is determined at the P ϩ 3 location by a Tyr(P) . We conducted structural modeling by superposition of the Arg SH2 domain with the structure of Lck bound to an 11-residue phosphopeptide (EPQpYEEIPIYL) derived from the hamster polyoma middle-T antigen (PDB 1LCJ) (35) (Fig.…”

Section: Arg and Abl Bind Cortactinmentioning

confidence: 97%

Two Amino Acid Residues Confer Different Binding Affinities of Abelson Family Kinase Src Homology 2 Domains for Phosphorylated Cortactin

Gifford

Liu

Mader

et al. 2014

Journal of Biological Chemistry

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Background: Abl family kinases bind different targets despite highly similar sequences. Results: Two residues in the Src homology (SH) 2 domain regulate binding to phosphorylated cortactin and modulate cell protrusion. Conclusion:The Arg SH2 domain binds with higher affinity than the Abl SH2 domain to phosphorylated cortactin. Significance: Slight sequence changes can cause affinity differences, leading to important functional changes in cellular interactions.

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“…The recently reported structure of Bcl-2 bound to an inhibitor (1YSW.pdb) [285] illustrates the site on the protein surface. (B) The p56lck SH2 domain bound to the pYEEI peptide (1LKK.pdb) [286] illustrates the hydrophobic pocket which was targeted in drug design. (C) Two chains of the S100B protein (blue,green) are complexed with the TRTK-12 peptide (1MWN.pdb) [287].…”

Section: P56lckmentioning

confidence: 99%

“…MacKerell, Hayashi and coworkers used virtual screening to identify non-peptide drug-like molecules targeting the Lck SH2 domain [270,286]. The SH2 domain contains a hydrophobic pocket in the pY+3 binding site (pY: phosphotyrosine), which mutational studies [271] and the crystal structures of different Src SH2 domains and ITAM peptides had identified as a site imparting binding specificity.…”

Section: P56lckmentioning

confidence: 99%

Computational Identification of Inhibitors of Protein-Protein Interactions

Zhong¹,

Macías²,

MacKerell³

2007

CTMC

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Abstract:The ability to control protein-protein interactions (PPIs) for therapeutic purposes is attractive since many processes in cells involve such interactions. Recent successes in the discovery of small molecules that target proteinprotein interactions for drug development have shown that targeting these interactions is indeed feasible. In the present review the use of computer-aided drug design (CADD) via database screening or docking algorithms for identifying inhibitors of protein-protein interactions is introduced. The principles of database screening and a practical protocol for targeting PPIs are described. The recent applications of these approaches to different systems involving protein-protein interactions, including BCL-2, S100B, ERK and p56lck, are presented and provide valuable examples of inhibitor discovery and design.

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Crystal Structures of the Human p56lckSH2 Domain in Complex with Two Short Phosphotyrosyl Peptides at 1.0 Å and 1.8 Å Resolution

Cited by 101 publications

References 0 publications

Calculation of absolute protein–ligand binding free energy from computer simulations

Calculation of absolute protein–ligand binding free energy from computer simulations

Two Amino Acid Residues Confer Different Binding Affinities of Abelson Family Kinase Src Homology 2 Domains for Phosphorylated Cortactin

Computational Identification of Inhibitors of Protein-Protein Interactions

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