The Protein Data Bank: Current status and future challenges

Abola, Enrique E.; Manning, N.O.; Prilusky, Jaime; Stampf, David; Sussman, Joel L.

doi:10.6028/jres.101.025

Cited by 23 publications

(15 citation statements)

References 17 publications

(17 reference statements)

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“…the first cysteine in the aa sequence is connected to the third one and the second cysteine to the fourth (31). The VCP and the factor H have a known three-dimensional structure that has been deposited in the Protein Data Bank (32). VCP entries 1VVD and 1VVE showed the closest homologies with the Sushi domain of TPO (aa 741 to 795).…”

Section: Resultsmentioning

confidence: 99%

Molecular Model, Calcium Sensitivity, and Disease Specificity of a Conformational Thyroperoxidase B-cell Epitope

Estienne¹,

Blanchet²,

Niccoli-Sire³

et al. 1999

Journal of Biological Chemistry

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While studying the humoral mechanisms involved in thyroid autoimmunity, we located a B-cell autoepitope in the extracellular C-terminal region of human thyroperoxidase. Structural modeling showed that this region encompasses both a Sushi-like and an epidermal growth factor-like domain, the flexible arrangement of which was putatively stabilized by calcium. The recombinant peptide was found to contain the previously identified conformational thyroperoxidase autoepitope. The occurrence of a calcium-induced conformational change was confirmed using a recombinant peptide monoclonal antibody, the decrease of which in binding to calcium-saturated thyroperoxidase was reversed by a chelating agent. The disease specificity of recombinant peptide, which was more frequently recognized by Hashimoto's than by Graves' patients, adds to its potential value as a diagnostic and preventive tool in the context of B-cell autoimmunity. Thyroperoxidase (TPO)1 plays a key role in the biosynthesis of thyroid hormones by catalyzing both the iodination of tyrosine residues and the coupling of some iodotyrosine residues in thyroglobulin to form tri-and tetraiodothyronines. It is a hemecontaining membrane enzyme which is expressed at the apical pole of thyrocytes facing the colloid space (1). TPO belongs to the mammalian peroxidase family, the members of which include myelo-, lacto-, eosinophil, and salivary peroxidases (2). Human TPO contains 933 amino acids (aa), and shows a large extracellular region consisting of 848 aa and five potential glycosylation sites, a short membrane-spanning region, and a 61-aa cytoplasmic tail. Most of the extracellular region of TPO shows a high degree of homology with myeloperoxidase (aa 1-739). The extracellular region close to the membrane anchorage domain shows homologies with the C4b complement component (aa 739 -794) and EGF (aa 794 -842) (3). The threedimensional structure of TPO is not yet known, and elucidating this point constitutes an important task for scientists investigating the peroxidase family and for immunologists focusing on autoimmunity questions because TPO is a major thyroid autoantigen.Autoantibodies (aAb) to TPO are the most sensitive and specific serological markers available for diagnosing autoimmune thyroid diseases. Like most antibodies to exogenous antigens, TPO aAb are produced by B lymphocytes via a T-celldependent mechanism involving specific cellular receptors and soluble cytokines. At the molecular level, however, the specificity of the autoimmune reaction relies on the recognition of TPO epitopes by T and B-cells (4). T-cell receptors recognize linear epitopes from processed TPO associated with class II molecules belonging to the major histocompatibility complex, which are co-expressed at the surface of antigen-presenting cells. By contrast, B-cell receptors, which are membrane-bound immunoglobulins, usually have a more stringent specificity and recognize conformational epitopes, i.e. they are highly dependent on the three-dimensional structure of the TPO molecule (5-7).

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Section: Resultsmentioning

confidence: 99%

Molecular Model, Calcium Sensitivity, and Disease Specificity of a Conformational Thyroperoxidase B-cell Epitope

Estienne¹,

Blanchet²,

Niccoli-Sire³

et al. 1999

Journal of Biological Chemistry

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“…We carried out MD simulations of myosin-ATP and myosin-ADP⅐Pi complexes, which are the initial and final states of ATP hydrolysis. The initial structures of these complexes were constructed on the basis of the x-ray crystallographic structure of the myosin-ADP/VO4 complex (code in Protein Data Bank (Abola et al, 1987(Abola et al, , 1996Bernstein et al, 1977): 1VOM (Smith and Rayment, 1996)). Because many amino acid residues were not determined in the coordinate data of this x-ray crystal structure, we repaired these amino acid residues (Ala205-Ser208, Asn711, Ala716-Ser719, and Asp724-Leu730) by using a homology module of Insight II (Insight II, version 95.0, Molecular Simulations Inc., San Diego).…”

Section: Construction Of the Initial Structurementioning

confidence: 99%

Theoretical Studies of the ATP Hydrolysis Mechanism of Myosin

Okimoto

Yamanaka

Ueno

et al. 2001

Biophysical Journal

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The ATP hydrolysis mechanism of myosin was studied using quantum chemical (QM) and molecular dynamics calculations. The initial model compound for QM calculations was constructed on the basis of the energy-minimized structure of the myosin(S1dc)-ATP complex, which was determined by molecular mechanics calculations. The result of QM calculations suggested that the ATP hydrolysis mechanism of myosin consists of a single elementary reaction in which a water molecule nucleophilically attacked gamma-phosphorus of ATP. In addition, we performed molecular dynamics simulations of the initial and final states of the ATP hydrolysis reaction, that is, the myosin-ATP and myosin-ADP.Pi complexes. These calculations revealed roles of several amino acid residues (Lys185, Thr186, Ser237, Arg238, and Glu459) in the ATPase pocket. Lys185 maintains the conformation of beta- and gamma-phosphate groups of ATP by forming the hydrogen bonds. Thr186 and Ser237 are coordinated to a Mg(2+) ion, which interacts with the phosphates of ATP and therefore contributes to the stabilization of the ATP structure. Arg238 and Glu459, which consisted of the gate of the ATPase pocket, retain the water molecule acting on the hydrolysis at the appropriate position for initiating the hydrolysis.

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“…entry 2zta; O'Shea et al, 1991! were used from the PDB~Bernstein et al, 1977;Abola et al, 1987Abola et al, , 1996 Only the coordinates of the first 31 residues of the 33 residue peptide that was crystallized were located in this structure. Rather than attempt to build in the missing residues by modeling, only the first 31 residues were used for these calculations.…”

Section: Methodsmentioning

confidence: 99%

Electrostatic interactions in the GCN4 leucine zipper: Substantial contributions arise from intramolecular interactions enhanced on binding

1999

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The GCN4 leucine zipper is a peptide homodimer that has been the subject of a number of experimental and theoretical investigations into the determinants of affinity and specificity. Here, we utilize this model system to investigate electrostatic effects in protein binding using continuum calculations. A particularly novel feature of the computations made here is that they provide an interaction-by-interaction breakdown of the electrostatic contributions to the free energy of docking that includes changes in the interaction of each functional group with solvent and changes in interactions between all pairs of functional groups on binding. The results show that~1! electrostatic effects disfavor binding by roughly 15 kcal0mol due to desolvation effects that are incompletely compensated in the bound state,~2! while no groups strongly stabilize binding, the groups that are most destabilizing are charged and polar side chains at the interface that have been implicated in determining binding specificity, and~3! attractive intramolecular interactions e.g., backbone hydrogen bonds! that are enhanced on binding due to reduced solvent screening in the bound state contribute significantly to affinity and are likely to be a general effect in other complexes. A comparison is made between the results obtained in an electrostatic analysis carried out calculationally and simulated results corresponding to idealized data from a scanning mutagenesis experiment. It is shown that scanning experiments provide incomplete information on interactions and, if overinterpreted, tend to overestimate the energetic effect of individual side chains that make attractive interactions. Finally, a comparison is made between the results available from a continuum electrostatic model and from a simpler surface-area dependent solvation model. In this case, although the simpler model neglects certain interactions, on average it performs rather well.

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The Protein Data Bank: Current status and future challenges

Cited by 23 publications

References 17 publications

Molecular Model, Calcium Sensitivity, and Disease Specificity of a Conformational Thyroperoxidase B-cell Epitope

Molecular Model, Calcium Sensitivity, and Disease Specificity of a Conformational Thyroperoxidase B-cell Epitope

Theoretical Studies of the ATP Hydrolysis Mechanism of Myosin

Electrostatic interactions in the GCN4 leucine zipper: Substantial contributions arise from intramolecular interactions enhanced on binding

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