KnotProt 2.0: a database of proteins with knots and other entangled structures

Dąbrowski-Tumański, Paweł; Rubach, Paweł; Goundaroulis, Dimos; Dorier, Julien; Sułkowski, Piotr; Millett, Kenneth C.; Rawdon, Eric J.; Stasiak, Andrzej; Sułkowska, Joanna I.

doi:10.1093/nar/gky1140

Cited by 86 publications

(131 citation statements)

References 31 publications

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“…We have shown that with the help of GISA it is possible to find cases of rare geometries in proteins, such as those studied in [2] and knots as identified with KnotProt [9]. GISA's command line tool scans formalize this, and more generally scores all the involved structures.…”

Section: Discussionmentioning

confidence: 99%

GISA: Using Gauss Integrals to identify rare conformations in protein structures

Grønbæk

Hamelryck

Røgen

2019

Preprint

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The native structure of a protein is important for its function, and therefore methods for exploring protein structures have attracted much research. However, rather few methods are sensitive to topologicgeometric features, the examples being knots, slipknots, lassos, links, and pokes, and with each method aimed only for a specific set of such configurations.We here propose a general method which transforms a structure into a "fingerprint of topological-geometric values" consisting in a series of real-valued descriptors from mathematical Knot Theory. The extent to which a structure contains unusual configurations can then be judged from this fingerprint. The method is therefore not confined to a particular pre-defined topology or geometry (like a knot or a poke), and so, unlike existing methods, it is general. To achieve this our new algorithm, GISA, as a key novelty produces the descriptors, so called Gauss integrals, not only for the full chains of a protein but for all its sub-chains, thereby allowing fingerprinting on any scale from local to global. The Gauss integrals are known to be effective descriptors of global protein folds.Applying GISA to a set of about 8000 high resolution structures (top8000), we first show how it enables swift identification of predefined geometries such as pokes and links. We then apply GISA with no restrictions on geometry, to show how it allows identifying rare conformations by finding rare invariant values only. In this unrestricted search, pokes and links are still found, but also knotted conformations, as well as more highly entangled configurations not previously described. Thus, applying the basic scan method in GISA's tool-box to the top8000 set, 10 known cases of knots are ranked as the top positive Gauss number cases, while placing at the top of the negative Gauss numbers 14 cases in cis-trans isomerases sharing a spatial motif of little secondary structure content, which possibly has gone unnoticed.

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Section: Discussionmentioning

confidence: 99%

GISA: Using Gauss Integrals to identify rare conformations in protein structures

Grønbæk

Hamelryck

Røgen

2019

Preprint

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“…We prepared distributions for the MD simulation and for all sets of SAM conformations extracted from protein-ligand complexes: unknotted proteins, knotted proteins, unknotted MTs, and knotted MTs. We obtained those complexes from PDB, and evaluated whether the protein is knotted or not using KnotProt 2.0 database [9].…”

Section: Methodsmentioning

confidence: 99%

“…The set of knotted methyltransferases (MTs) is the largest group of all known knotted proteins, which structures comprise now about 2% of PDB’s deposits. Interestingly, all of the known structures of knotted MTs possess the same type of the knotted region, which is a deep trefoil knot [8, 9]. The knot is located in the middle of the protein chain, is tight (about 45 amino acids), and has long tails (Fig.…”

Section: Introductionmentioning

confidence: 99%

Restriction of S-adenosylmethionine conformational freedom by knotted protein binding sites

Perlinska

Stasiulewicz

Nawrocka

et al. 2019

Preprint

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S-adenosylmethionine (SAM) is one of the most important enzyme substrates. It is vital for the function of various proteins, including large group of methyltransferases (MTs). Intriguingly, some bacterial and eukaryotic MTs, while catalysing the same reaction, possess significantly different topologies, with the former being a knotted one. Here, we conducted a comprehensive analysis of SAM conformational space and factors that affect its vastness. We investigated SAM in two forms: free in water (via NMR studies and explicit solvent simulations) and bound to proteins (based on all data available in the PDB). We identified structural descriptors -angles which show the major differences in SAM conformation between unknotted and knotted methyltransferases. Moreover, we report that this is caused mainly by a characteristic for knotted MTs tight binding site formed by the knot and the presence of adenine-binding loop. Additionally, we elucidate conformational restrictions imposed on SAM molecules by other protein groups in comparison to conformational space in water. Author summaryThe topology of a folded polypeptide chain has great impact on the resulting protein function and its interaction with ligands. Interestingly, topological constraints appear to affect binding of one of the most ubiquitous substrates in the cell, S-adenosylmethionine (SAM), to its target proteins. Here, we demonstrate how binding sites of specific proteins restrict SAM conformational freedom in comparison to its unbound state, with a special interest in proteins with non-trivial topology, including an exciting group of knotted methyltransferases. Using a vast array of computational methods combined with NMR experiments, we identify key structural features of knotted methyltransferases that impose unorthodox SAM conformations. We compare them with the characteristics of standard, unknotted SAM binding proteins. These results are significant for understanding differences between analogous, yet topologically different enzymes, as well as for future rational drug design. October 7, 2019 1/22 1 S-adenosylmethionine (SAM or AdoMet) is an ubiquitous molecule and the second most 2 widely used enzyme substrate after ATP [1]. It is utilized in many different chemical 3 reactions, including transfer of the methyl group. It acts as methyl donor for a variety 4 of methyltransferases (MTs), involved in methylation of small molecules [2], proteins [3], 5 DNA [4], and RNA [5]. Interestingly, SAM binds not only to proteins but also to RNA -6 it is a substrate for riboswitches [6]. 7The diversity of molecules capable of binding SAM is great not only in a variety of 8 performed functions, but also in their structure and topology. In the case of 9 SAM-dependent methyltransferases, the proteins are divided into five classes, each with 10 a different fold, including a knotted one [7]. The set of knotted methyltransferases 11 (MTs) is the largest group of all known knotted proteins, which structures comprise now 12 about 2% of PDB's deposits. Interestingly, all of t...

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“…Independently of these methodological advances, the overall picture of the topological properties of the known native conformations is by now well established (16,17). The systematic application of knot detection methodologies based on the KMT algorithm to all available protein entries in the PDB revealed that about 1% correspond to knotted proteins (10,16).…”

Section: Introductionmentioning

confidence: 99%

Knotted proteins: Tie etiquette in structural biology

Nunes¹,

Faísca²

2020

Topology and Geometry of Biopolymers

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A small fraction of all protein structures characterized so far are entangled. The challenge of understanding the properties of these knotted proteins, and the why and the how of their natural folding process, has been taken up in the past decade with different approaches, such as structural characterization, in vitro experiments, and simulations of protein models with varying levels of complexity. The simplest among these are the lattice Gō models, which belong to the class of structure-based models, i.e., models that are biased to the native structure by explicitly including structural data. In this review we highlight the contributions to the field made in the scope of lattice Gō models, putting them into perspective in the context of the main experimental and theoretical results and of other, more realistic, computational approaches.

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KnotProt 2.0: a database of proteins with knots and other entangled structures

Cited by 86 publications

References 31 publications

GISA: Using Gauss Integrals to identify rare conformations in protein structures

GISA: Using Gauss Integrals to identify rare conformations in protein structures

Restriction of S-adenosylmethionine conformational freedom by knotted protein binding sites

Knotted proteins: Tie etiquette in structural biology

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