ModLoop: automated modeling of loops in protein structures

Fiser, András; Šali, Andrej

doi:10.1093/bioinformatics/btg362

Cited by 731 publications

(578 citation statements)

References 19 publications

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“…Loop regions were optimized with MODLOOP (27), and optimal side chain rotamers were found using SCWRL (28). Peptides were docked with a simulated annealing based approach that was shown to dock 5-8-amino acid long peptides to x-ray structures with root mean square deviation Ͻ2 Å, and to homology models with root mean square deviation Ͻ3 Å compared with the corresponding crystal structures.…”

Section: Methodsmentioning

confidence: 99%

Molecular Determinants for the Complex Binding Specificity of the PDZ Domain in PICK1

Madsen

Beuming

Niv

et al. 2005

Journal of Biological Chemistry

143

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PICK1 (protein interacting with C kinase 1) contains a single PDZ domain known to mediate interaction with the C termini of several receptors, transporters, ion channels, and kinases. In contrast to most PDZ domains, the PICK1 PDZ domain interacts with binding sequences classifiable as type I (terminating in (S/T)X⌽; X, any residue) as well as type II (⌽X⌽; ⌽, any hydrophobic residue). To enable direct assessment of the affinity of the PICK1 PDZ domain for its binding partners we developed a purification scheme for PICK1 and a novel quantitative binding assay based on fluorescence polarization. Our results showed that the PICK1 PDZ domain binds the type II sequence presented by the human dopamine transporter (-WLKV) with an almost 15-fold and >100-fold higher affinity than the type I sequences presented by protein kinase C␣ (-QSAV) and the ␤ 2 -adrenergic receptor (-DSLL), respectively. Mutational analysis of Lys 83 in the ␣B1 position of the PDZ domain suggested that this residue mimics the function of hydrophobic residues present in this position in regular type II PDZ domains. The PICK1 PDZ domain was moreover found to prefer small hydrophobic residues in the C-terminal P(0) position of the ligand. Molecular modeling predicted a rank order of (Val > Ile > Leu) that was verified experimentally with up to a ϳ16-fold difference in binding affinity between a valine and a leucine in P(0). The results define the structural basis for the unusual binding pattern of the PICK1 PDZ domain by substantiating the critical role of the ␣B1 position (Lys 83 ) and of discrete side chain differences in position P(0) of the ligands.With over 540 domains in more than 300 different proteins, PDZ (PSD-95/Disc-large/ZO-1 homology) 1 domains are among the most common protein domains in the human genome (1-3). They mediate cellular protein-protein interactions and serve important roles in protein targeting and in the assembly of protein complexes (1, 2). PICK1 (protein interacting with C kinase 1) contains a single N-terminal PDZ domain and was originally identified as an interaction partner for protein kinase C␣ (PKC␣) (5). In addition to its N-terminal PDZ domain, PICK1 contains a coiled-coil domain (residue 145-165 in rat PICK1) that is believed to mediate dimerization of PICK1 (6), followed by a region bearing homology to Arfaptin 1 and 2 (residue 152-362), and a C-terminal acidic cluster (residue 381-389). Although PICK1 was named for its interaction with PKC␣, it rapidly became clear that it had multiple interaction partners. At the current stage, the PDZ domain of PICK1 has been shown to mediate interaction with a broad range of proteins including receptor tyrosine kinases, ionotropic glutamate receptors of the L-␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate subtypes, metabotropic glutamate receptors, ion channels, G protein-coupled receptors, aquaporins, transmembrane transporters, and ADPribosylation factors (see Table I and Ref. 7). PICK1 has been proposed to play a key role in clustering several o...

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Section: Methodsmentioning

confidence: 99%

Molecular Determinants for the Complex Binding Specificity of the PDZ Domain in PICK1

Madsen

Beuming

Niv

et al. 2005

Journal of Biological Chemistry

143

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“…The structures of each are similar in core regions but diverge in loop regions, particularly loop A (residues 67-157). Refinement of loop A was attempted using ModLoop (27,28), which predicts loop folding based on spatial restraints instead of homology. However, resulting structures were not improved, as judged by structure quality assessments (see below for methodological details).…”

Section: Alignment and Selection Of Crystal Structure Templates Formentioning

confidence: 99%

Structural Determinants Allowing Transferase Activity in SENSITIVE TO FREEZING 2, Classified as a Family I Glycosyl Hydrolase

Roston

Wang

Kuhn

et al. 2014

Journal of Biological Chemistry

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Background: SENSITIVE TO FREEZING 2 (SFR2) is classified as a glycosyl hydrolase, and by using glycosyltransferase activity, it modifies membrane lipids to promote freeze tolerance. Results: Although the active site of SFR2 is identical to hydrolases, adjacent loop regions contribute to its transferase activity. Conclusion: Transferase activity evolved by modifications external to the core catalytic site. Significance: Defined structure-function relationships will inform engineering of transferases and freeze tolerance.

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“…This structure was validated with the help of Ramachandran plot using PDBsum/Rampage. The process of loop modeling and successive validation was carried on until an optimized structured model of protein was obtained [35][36][37][38].…”

Section: Loop Modelingmentioning

confidence: 99%

Structure Prediction and in Silico Designing of Drugs Against Kallikrein Protein 12

Devgan¹

2017

Int J Curr Pharm Sci

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Objective: Human Kallikrein protein 12 (hK12) might serve as a novel diagnostic and prognostic biomarker, as well as a potential therapeutic target, in gastric cancer. Methods:In this work, a theoretical model of hK12 receptor protein was generated using the concepts of homology modeling and loop modeling. The resulting model was validated with Ramachandran plot analysis. The ligands generated with the help of Drug bank were docked against hK12 receptor protein using AutoDock Vina in PyRx 0.8. The structure of ligand DB04786 (Suramin), with least binding energy, was varied by using ACD/ChemSketch 8.0 and the docking was done for the resulting 16 new ligands. Results:The results indicated that the ligand10 bears the minimum binding energy (-12.3 Kcal/mol) with the target protein and thus the prospects of binding are high. The results also clearly demonstrated that the in silico molecular docking studies of selected ligands, i.e., suramin, ligands 5, 6, 10 and 16 with hK12 protein exhibited favourable binding interactions and warranted. Conclusion:Further studies needed for the development of potent inhibitors for the overexpression of hK12 protein making the management of gastric cancer more efficient.

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ModLoop: automated modeling of loops in protein structures

Abstract: The server is freely accessible to academic users at http://salilab.org/modloop

Cited by 731 publications

References 19 publications

Molecular Determinants for the Complex Binding Specificity of the PDZ Domain in PICK1

Molecular Determinants for the Complex Binding Specificity of the PDZ Domain in PICK1

Structural Determinants Allowing Transferase Activity in SENSITIVE TO FREEZING 2, Classified as a Family I Glycosyl Hydrolase

Structure Prediction and in Silico Designing of Drugs Against Kallikrein Protein 12

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