STRUCTFAST: Protein sequence remote homology detection and alignment using novel dynamic programming and profile–profile scoring

Debe, Derek A.; Danzer, Joseph F.; Goddard, William A.; Poleksić, Aleksandar

doi:10.1002/prot.21049

Cited by 32 publications

(17 citation statements)

References 29 publications

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“…(9) CABS proved very accurate in protein folding 7,8 and protein structure predictions (ranked as best, or one of the best, among other approaches in CASP6 blind prediction experiments). (10)…”

Section: Methodsmentioning

confidence: 99%

Simulation of Chaperonin Effect on Protein Folding: A Shift from Nucleation–Condensation to Framework Mechanism

Kmiecik

Koliński

2011

J. Am. Chem. Soc.

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The iterative annealing mechanism (IAM) of chaperonin-assisted protein folding is explored in a framework of a well-established coarse-grained protein modeling tool, which enables the study of protein dynamics in a time-scale well beyond classical all-atom molecular mechanics. The chaperonin mechanism of action is simulated for two paradigm systems of protein folding, B domain of protein A (BdpA) and B1 domain of protein G (GB1), and compared to chaperonin-free simulations presented here for BdpA and recently published for GB1. The prediction of the BdpA transition state ensemble (TSE) is in perfect agreement with experimental findings. It is shown that periodic distortion of the polypeptide chains by hydrophobic chaperonin interactions can promote rapid folding and leads to a decrease in folding temperature. It is also demonstrated how chaperonin action prevents kinetically trapped conformations and modulates the observed folding mechanisms from nucleation–condensation to a more framework-like.

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Section: Methodsmentioning

confidence: 99%

Simulation of Chaperonin Effect on Protein Folding: A Shift from Nucleation–Condensation to Framework Mechanism

Kmiecik

Koliński

2011

J. Am. Chem. Soc.

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“…However, the results should be viewed as our current stage of knowledge, based on the available structural body of the PDB. The vast majority of models are well within or above the required template identity to generate reliable homology models for the purpose of comparing sites18 - in particular for the profile-profile STRUCTFAST method used here 46,63. We can expect this picture to further be refined as more structures become available.…”

Section: Resultsmentioning

confidence: 97%

Knowledge-Based Characterization of Similarity Relationships in the Human Protein−Tyrosine Phosphatase Family for Rational Inhibitor Design

Vidović

Schürer

2009

J. Med. Chem.

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Tyrosine phosphorylation, controlled by the coordinated action of protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs), is a fundamental regulatory mechanism of numerous physiological processes. PTPs are implicated in a number of human diseases and their potential as prospective drug targets is increasingly being recognized. Despite their biological importance, until now no comprehensive overview has been reported describing how all members of the human PTP family are related. Here we review the entire human PTP family and present a systematic knowledge-based characterization of global and local similarity relationships, which are relevant for the development of small molecule inhibitors. We use parallel homology modeling to expand the current PTP structure space and analyze the human PTPs based on local three-dimensional catalytic sites and domain sequences. Furthermore, we demonstrate the importance of binding site similarities in understanding cross-reactivity and inhibitor selectivity in the design of small molecule inhibitors.

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“…Snapshots of key elements in a structural model for hCaSR: subdomain structure of the ECD, hinge region in the VFT, and position of cysteine 482. Model was developed using the StructFast algorithm (Eidogen-Sertanty, Inc., Oceanside, CA) (Debe et al, 2006) on the basis of the structure of mGluR3 (Muto et al, 2007;PDB ID: 2E4U), and displayed with PyMOL (The PyMOL Molecular Graphics System, Version 1.3, Schrödinger, LLC). (A) High level perspective of entire ECD of the hCaSR viewed along the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Critical Cysteine Residues in Both the Calcium-Sensing Receptor and the Allosteric Activator AMG 416 Underlie the Mechanism of Action

et al. 2015

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AMG 416 is a novel D-amino acid-containing peptide agonist of the calcium-sensing receptor (CaSR) that is being evaluated for the treatment of secondary hyperparathyroidism in chronic kidney disease patients receiving hemodialysis. The principal amino acid residues and their location in the CaSR that accommodate AMG 416 binding and mode of action have not previously been reported. Herein we establish the importance of a pair of cysteine residues, one from AMG 416 and the other from the CaSR at position 482 (Cys482), and correlate the degree of disulfide bond formation between these residues with the pharmacological activity of AMG 416. KP-2067, a form of the CaSR agonist peptide, was included to establish the role of cysteine in vivo and in disulfide exchange. Studies conducted with AMG 416 in pigs showed a complete lack of pharmacodynamic effect and provided a foundation for determining the peptide agonist interaction site within the human CaSR. Inactivity of AMG 416 on the pig CaSR resulted from a naturally occurring mutation encoding tyrosine for cysteine (Cys) at position 482 in the pig CaSR. Replacing Cys482 in the human CaSR with serine or tyrosine ablated AMG 416 activity. Decidedly, a single substitution of cysteine for tyrosine at position 482 in the native pig CaSR provided a complete gain of activity by the peptide agonist. Direct evidence for this disulfide bond formation between the peptide and receptor was demonstrated using a mass spectrometry assay. The extent of disulfide bond formation was found to correlate with the extent of receptor activation. Notwithstanding the covalent basis of this disulfide bond, the observed in vivo pharmacology of AMG 416 showed readily reversible pharmacodynamics.

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STRUCTFAST: Protein sequence remote homology detection and alignment using novel dynamic programming and profile–profile scoring

Cited by 32 publications

References 29 publications

Simulation of Chaperonin Effect on Protein Folding: A Shift from Nucleation–Condensation to Framework Mechanism

Simulation of Chaperonin Effect on Protein Folding: A Shift from Nucleation–Condensation to Framework Mechanism

Knowledge-Based Characterization of Similarity Relationships in the Human Protein−Tyrosine Phosphatase Family for Rational Inhibitor Design

Critical Cysteine Residues in Both the Calcium-Sensing Receptor and the Allosteric Activator AMG 416 Underlie the Mechanism of Action

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