Systematic Investigation of Halogen Bonding in Protein–Ligand Interactions

Hardegger, Leo A.; Kuhn, Bernd; Spinnler, Beat; Anselm, Lilli; Ecabert, Robert; Stihle, M.; Gsell, Bernard; Thoma, Ralf; Diez, Joachim; Benz, Jörg; Plancher, Jean‐Marc; Hartmann, Guido; Banner, David W.; Haap, Wolfgang; Diederich, François

doi:10.1002/anie.201006781

Cited by 434 publications

(417 citation statements)

References 28 publications

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“…Access to the active site was prevented by inhibitors including the propeptide, which explains the crystal structures of khCL complex with the p41 fragment [11], the small molecule complexes rhCL_1 and rhCL_3 [14,29] and the proenzyme structure [10]. However, among the Q scoring, quality of alignment, which took both the alignment length and RMSD into account; Ca RMSD, root-mean-square deviation, calculated between Ca-atoms; N-align, number of matched residues.…”

Section: Discussionmentioning

confidence: 99%

“…a part of the physiological substrate histone H3 and human cathepsin L by crystallizing the complex with a catalytic mutant of the enzyme and elucidating its structure [16]. Refinement confirmed the positioning of only three amino acids from the histone H3 [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] peptide. Our crystal packing analysis suggested that there is not enough space to accommodate all 14 peptide residues in the available space in the active site cleft.…”

Section: Abstract: Cathepsin; Cysteine Cathepsin; Substrate Interactionmentioning

confidence: 99%

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Caught in the act: the crystal structure of cleaved cathepsin L bound to the active site of Cathepsin L

Sosnowski

Turk

2016

FEBS Letters

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Cathepsin L is a ubiquitously expressed papain-like cysteine protease involved in the endosomal degradation of proteins and has numerous roles in physiological and pathological processes, such as arthritis, osteoporosis, and cancer. Insight into the specificity of cathepsin L is important for elucidating its physiological roles and drug discovery. To study interactions with synthetic ligands, we prepared a presumably inactive mutant and crystallized it. Unexpectedly, the crystal structure determined at 1.4 A revealed that the cathepsin L molecule is cleaved, with the cleaved region trapped in the active site cleft of the neighboring molecule. Hence, the catalytic mutant demonstrated low levels of catalytic activity.

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Section: Discussionmentioning

confidence: 99%

Section: Abstract: Cathepsin; Cysteine Cathepsin; Substrate Interactionmentioning

confidence: 99%

Caught in the act: the crystal structure of cleaved cathepsin L bound to the active site of Cathepsin L

Sosnowski

Turk

2016

FEBS Letters

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“…Moreover, halogenated coumpounds are often encountered in medicinal chemistry [79] and drug discovery. [80] Quantum Chemistry approaches have revealed a sigma-hole along the axis defined by the halogen atom and the acceptor. This can be studied thanks to the Molecular Electrostatic Potentials, showing the charge distribution as well as the nature of the interaction as electrostatics and charge transfer driven.…”

Section: Halogen Bondingmentioning

confidence: 99%

A Complete NCI Perspective: From New Bonds to Reactivity

Narth¹,

Maroun²,

Boto³

et al. 2016

Challenges and Advances in Computational Chemistry and Physics

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The Non-Covalent Interaction (NCI) index is a new topological tool that has recently been added to the theoretical chemist's arsenal. NCI fills a gap that existed within topological methods for the visualization of non-covalent interactions. Based on the electron density and its derivatives, it is able to reveal both attractive and repulsive interactions in the shape of isosurfaces, whose color code reveals the nature of the interaction. It is interesting to note that NCI can even be calculated at the promolecular level, making it a suitable tool for big systems, such as proteins or DNA. Within this chapter we will review the main characteristics of NCI, its similarities with and differences from previous approaches. Special attention will be paid to the visualization of new interaction types. Being based on the electron density, NCI is not only very stable with respect to the calculation method, but it is also a suitable tool for detecting new bonding mechanisms, since all such mechanisms should have a detectable effect on the electron density. This type of approach overcomes the limitations of bond definition, revealing all interaction types, irrespective of whether they have a name or have previously been identified. Finally, we will show how this tool can be used to understand chemical change along a chemical reaction. We will show several examples of torquoselectivity and put forward an explanation of selectivity based on secondary interactions which is complementary to the historical orbital approach.A complete NCI perspective: from new bonds to reactivity 3

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“…Halogen bonds form between nucleophilic acceptors, such as anions, and highly localized positive-charge density on halogen atoms appearing on the side opposite to the covalent bond [13][14][15][16][17][18][19][20][21][22] . They are most prominent with iodine atoms but occur, to a lesser extent, also with the less polarizable bromine, chlorine, and even fluorine (Fig.…”

mentioning

confidence: 99%

“…Routinely exploited in crystal engineering 14 , halogen bonds are attracting only recently some attention for rational drug design 16 , anion binding 17,18 and catalysis 19,20 . Whereas the special behaviour of molecular iodine (bp = 184 °C) has been noticed early on 21,22 , contributions of organic halogen bonds to the transport of anion across lipid bilayer membranes have been suspected last year, for the first time 13 .…”

mentioning

confidence: 99%

Transmembrane anion transport mediated by halogen-bond donors

et al. 2012

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In biology and chemistry, the transport of anions across lipid bilayer membranes is usually achieved by sophisticated supramolecular architectures. significant size reduction of transporters is hampered by the intrinsically hydrophilic nature of typical anion-binding functionalities, hydrogen-bond donors or cations. To maximize the atom efficiency of anion transport, the hydrophobic nature, directionality, and strength of halogen bonds seem promising. unlike the ubiquitous, structurally similar hydrogen bonds, halogen bonds have not been explored for anion transport. Here we report that transport across lipid bilayers can be achieved with small perfluorinated molecules that are equipped with strong halogen-bond donors. Transport is observed with trifluoroiodomethane (boiling point = − 22 °C); that is, it acts as a 'single-carbon' transporter. Contrary to the destructive action of small-molecule detergents, transport with halogen bonds is leakage-free, cooperative, non-ohmic and highly selective, with anion/cation permeability ratios < 37.

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Systematic Investigation of Halogen Bonding in Protein–Ligand Interactions

Cited by 434 publications

References 28 publications

Caught in the act: the crystal structure of cleaved cathepsin L bound to the active site of Cathepsin L

Caught in the act: the crystal structure of cleaved cathepsin L bound to the active site of Cathepsin L

A Complete NCI Perspective: From New Bonds to Reactivity

Transmembrane anion transport mediated by halogen-bond donors

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