SymmRef: A flexible refinement method for symmetric multimers

Mashiach-Farkash, Efrat; Nussinov, Ruth; Wolfson, Haim J.

doi:10.1002/prot.23082

Cited by 16 publications

(18 citation statements)

References 44 publications

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“…Symmetric complex structure minimization by docking is a practical alternative but usually requires the number of subunits to be known, and an unambiguous assignment of the interprotomer restraints to specific pairs of protomers. This approach was mainly demonstrated for homo-oligomers with point symmetry where only rotations are involved (39)(40)(41). Thus far, only few high-resolution structures of helical assemblies from NMR data have been published (9)(10)(11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

Structure determination of helical filaments by solid-state NMR spectroscopy

Bardiaux

Ahmed

et al. 2016

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

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The controlled formation of filamentous protein complexes plays a crucial role in many biological systems and represents an emerging paradigm in signal transduction. The mitochondrial antiviral signaling protein (MAVS) is a central signal transduction hub in innate immunity that is activated by a receptor-induced conversion into helical superstructures (filaments) assembled from its globular caspase activation and recruitment domain. Solid-state NMR (ssNMR) spectroscopy has become one of the most powerful techniques for atomic resolution structures of protein fibrils. However, for helical filaments, the determination of the correct symmetry parameters has remained a significant hurdle for any structural technique and could thus far not be precisely derived from ssNMR data. Here, we solved the atomic resolution structure of helical MAVS CARD filaments exclusively from ssNMR data. We present a generally applicable approach that systematically explores the helical symmetry space by efficient modeling of the helical structure restrained by interprotomer ssNMR distance restraints. Together with classical automated NMR structure calculation, this allowed us to faithfully determine the symmetry that defines the entire assembly. To validate our structure, we probed the protomer arrangement by solvent paramagnetic resonance enhancement, analysis of chemical shift differences relative to the solution NMR structure of the monomer, and mutagenesis. We provide detailed information on the atomic contacts that determine filament stability and describe mechanistic details on the formation of signaling-competent MAVS filaments from inactive monomers.solid-state NMR | protein structure | grid search | MAVS | innate immunity

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Section: Discussionmentioning

confidence: 99%

Structure determination of helical filaments by solid-state NMR spectroscopy

Bardiaux

Ahmed

et al. 2016

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

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“…However, ab initi o docking requires the structure of the monomer to be known independently from that of the oligomer, which is very uncommon. Mashiach‐Farkash et al . cite 16 examples, and show that symmetric docking procedures, including their own, yield near‐native models of 4–7 of them.…”

Section: Discussionmentioning

confidence: 99%

Structural templates for modeling homodimers

2013

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Oligomeric proteins are more abundant in nature than monomeric proteins, and involved in all biological processes. In the absence of an experimental structure, their subunits can be modeled from their sequence like monomeric proteins, but reliable procedures to build the oligomeric assembly are scarce. Template-based methods, which start from known protein structures, are commonly applied to model subunits. We present a method to model homodimers that relies on a structural alignment of the subunits, and test it on a set of 511 target structures recently released by the Protein Data Bank, taking as templates the earlier released structures of 3108 homodimeric proteins (H-set), and 2691 monomeric proteins that form dimer-like assemblies in crystals (M-set). The structural alignment identifies a H-set template for 97% of the targets, and in half of the cases, it yields a correct model of the dimer geometry and residue-residue contacts in the target. It also identifies a M-set template for most of the targets, and some of the crystal dimers are very similar to the target homodimers. The procedure efficiently detects homology at low levels of sequence identities, and points to erroneous quaternary structures in the Protein Data Bank. The high coverage of the target set suggests that the content of the Protein Data Bank already approaches the structural diversity of protein assemblies in nature, and that template-based methods should become the choice method for modeling oligomeric as well as monomeric proteins.

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“…The very efficient docking suite by Wolfson and colleagues [24] is split into different applications that perform specific tasks: PatchDock [42] generates rigidbody models based on geometric hashing techniques, FlexDock [77] introduces flexibility around hinges and FireDock [24] refines the docked models. Other specific tools deal with symmetrical assemblies [42,78]. PatchDock can use interface information in a similar way to ClusPro, allowing 'attractive' and 'repulsive' regions to be defined, as well as offering the possibility of setting distance constraints.…”

Section: State-of-the-art Of Integrative Modeling Softwarementioning

confidence: 99%

Integrative computational modeling of protein interactions

Rodrigues

Bonvin

2014

The FEBS Journal

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Protein interactions define the homeostatic state of the cell. Our ability to understand these interactions and their role in both health and disease is tied to our knowledge of the 3D atomic structure of the interacting partners and their complexes. Despite advances in experimental method of structure determination, the majority of known protein interactions are still missing an atomic structure. High‐resolution methods such as X‐ray crystallography and NMR spectroscopy struggle with the high‐throughput demand, while low‐resolution techniques such as cryo‐electron microscopy or small‐angle X‐ray scattering provide data that are too coarse. Computational structure prediction of protein complexes, or docking, was first developed to complement experimental research and has since blossomed into an independent and lively field of research. Its most successful products are hybrid approaches that combine powerful algorithms with experimental data from various sources to generate high‐resolution models of protein complexes. This minireview introduces the concept of docking and docking with the help of experimental data, compares and contrasts the available integrative docking methods, and provides a guide for the experimental researcher for what types of data and which particular software can be used to model a protein complex.

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SymmRef: A flexible refinement method for symmetric multimers

Cited by 16 publications

References 44 publications

Structure determination of helical filaments by solid-state NMR spectroscopy

Structure determination of helical filaments by solid-state NMR spectroscopy

Structural templates for modeling homodimers

Integrative computational modeling of protein interactions

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