Hydrogen bonding motifs of protein side chains: Descriptions of binding of arginine and amide groups

Shimoni, Liat; Glusker, Jenny P.

doi:10.1002/pro.5560040109

Cited by 55 publications

(44 citation statements)

References 29 publications

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“…Using a series of deletion mutants fused to GST, amino acids 30 to 37 (IAQQNQSR) were shown to contribute most strongly to N-N interactions. Due to the high concentration of amide containing the residues asparagine (N) and glutamine (Q) in this stretch of amino acids, it is possible that N-N interactions occur partly through hydrogen bonding (40,52). This domain corresponds to a relatively hydrophilic region of the N protein and therefore is likely to be exposed to the aqueous environment rather than sequestered internally.…”

Section: Discussionmentioning

confidence: 99%

Homo-Oligomerization of the Porcine Reproductive and Respiratory Syndrome Virus Nucleocapsid Protein and the Role of Disulfide Linkages

Wootton

Yoo

2003

J Virol

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As a step toward understanding the assembly pathway of the porcine reproductive and respiratory syndrome virus (PRRSV), the oligomeric properties of the nucleocapsid (N) protein were investigated. In this study, we have demonstrated that under nonreducing conditions the N protein forms disulfide-linked homodimers. However, inclusion of an alkylating agent (N-ethylmaleimide [NEM]) prevented disulfide bond formation, suggesting that these intermolecular disulfide linkages were formed as a result of spurious oxidation during cell lysis. In contrast, N protein homodimers isolated from extracellular virions were shown to have formed NEM-resistant intermolecular disulfide linkages, the function of which is probably to impart stability to the virion. Pulse-chase analysis revealed that N protein homodimers become specifically disulfide linked within the virus-infected cell, albeit at the later stages of infection, conceivably when the virus particle buds into the oxidizing environment of the endoplasmic reticulum. Moreover, NEM-resistant disulfide linkages were shown to occur only during productive PRRSV infection, since expression of recombinant N protein did not result in the formation of NEM-resistant disulfide-linked homodimers. Mutational analysis indicated that of the three conserved cysteine residues in the N protein, only the cysteine at position 23 was involved in the formation of disulfide linkages. The N protein dimer was shown to be stable both in the presence and absence of intermolecular disulfide linkages, indicating that noncovalent interactions also play a role in dimerization. Nondisulfide-mediated N protein interactions were subsequently demonstrated both in vitro by the glutathione S-transferase (GST) pull-down assay and in vivo by the mammalian two-hybrid assay. Using a series of N protein deletion mutants fused to GST, amino acids 30 to 37 were shown to be essential for N-N interactions. Furthermore, since RNase A treatment markedly decreased N protein-binding affinity, it appears that at least in vitro, RNA may be involved in bridging N-N interactions. In cross-linking experiments, the N protein was shown to assemble into higher-order structures, including dimers, trimers, tetramers, and pentamers. Together, these findings demonstrate that the N protein possesses self-associative properties, and these likely provide the basis for PRRSV nucleocapsid assembly.Porcine reproductive and respiratory syndrome is a widespread disease causing respiratory disorders in young pigs and reproductive failure in sows and gilts. The disease was first recognized in North America in 1987 (reviewed in reference 15), and shortly thereafter, the etiological agent was isolated from pigs in Europe (45) and in North America (2, 7). North American and European isolates of porcine reproductive and respiratory syndrome virus (PRRSV) correspond to two distinct genotypes (25,27,30), which exhibit significant antigenic differences (31, 46). Consequently, PRRSV has been divided into two subspecies, European (type I) and North Am...

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Section: Discussionmentioning

confidence: 99%

Homo-Oligomerization of the Porcine Reproductive and Respiratory Syndrome Virus Nucleocapsid Protein and the Role of Disulfide Linkages

Wootton

Yoo

2003

J Virol

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“…6 One significant feature of these side chains is their tendency to form a bidentate hydrogenbonding pattern (two hydrogen bonds resulting in a ring structure, as in Figure 2), which in the case of protein-nucleic acid interactions is described as R 2 2 (9). 6 Bidentate hydrogen bonds are important because they are more specific than monodentate hydrogen bonds.…”

Section: Introductionmentioning

confidence: 99%

Energies and Geometries of Isographic Hydrogen-Bonded Networks. 1. The (8) Graph Set

1996

Self Cite

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The bidentate hydrogen-bonding patterns frequently formed by the side chains of the amino acids arginine, asparagine, and glutamine can be described, using graph-set notation, as R 2 2 (8) (ring pattern of eight atoms with two donor and two acceptor hydrogen bonds). It is shown that this hydrogen-bonding pattern is present in approximately 34% of the high-resolution crystal structures in the Cambridge Structural Database (CSD) that have the potential to form this particular pattern. Most of these crystal structures involve an interaction between two amide groups, but a significant number involve an interaction between an amidinium cation and a carboxylate anion. The mean H‚‚‚O bond distances and the N-H‚‚‚O bond angles found for these two types of interaction are nearly the same. Ab initio molecular orbital calculations are used to investigate the structure, charge distribution, and decomposition enthalpies of several gas phase hydrogen-bonded complexes which have these types of R 2 2 (8) interactions. Calculated H‚‚‚O bond distances and N-H‚‚‚O bond angles for the amide-amide type of interaction lie between the upper and lower bounds for these geometrical parameters found in the CSD. On the other hand, calculated H‚‚‚O bond distances for several amidinium ion-carboxylate ion structures are found to be significantly less than the lower bound of this distance found in the CSD study, apparently due to a strong electrostatic interaction between the ion fragments in the gas phase.

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“…A similar interaction is seen with LY404187 (49) bound to GluA2 i (8). Strong hydrogen bonding can occur between two amides (50) and has been shown to be responsible for driving oligomerization of transmembrane leucine zippers (51). The distances between the interacting amides in the PEPA-bound structure support a bidentate hydrogen-bonding pattern, which is much stronger and more specific than a typical hydrogen bond.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Flop Selectivity and Subsite Recognition for an AMPA Receptor Allosteric Modulator: Structures of GluA2 and GluA3 in Complexes with PEPA

2010

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Glutamate receptors are important potential drug targets for cognitive enhancement and the treatment of schizophrenia in part because they are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system. One approach to the application of therapeutic agents to the AMPA subtype of glutamate receptors is the use of allosteric modulators, which promote dimerization by binding to a dimer interface thereby reducing desensitization and deactivation. AMPA receptors exist in two alternatively spliced variants (flip and flop) that differ in desensitization and receptor activation profiles. Most of the structural information on modulators of the AMPA receptor target the flip subtype. We report here the crystal structure of the flop-selective allosteric modulator, PEPA, bound to the binding domains of the GluA2 and GluA3 flop isoforms of AMPA receptors. Specific hydrogen bonding patterns can explain the preference for the flop isoform. This includes a bidentate hydrogen bonding pattern between PEPA and N754 of the flop isoforms of GluA2 and GluA3 (the corresponding position in the flip isoform is S754). Comparison with other allosteric modulators provides a framework for the development of new allosteric modulators with preferences for either the flip or flop isoforms. In addition to interactions with N/S754, specific interactions of the sulfonamide with conserved residues in the binding site are characteristics of a number of allosteric modulators. These, in combination, with variable interactions with five subsites on the binding surface lead to different stoichiometries, orientations within the binding pockets, and functional outcomes.

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Hydrogen bonding motifs of protein side chains: Descriptions of binding of arginine and amide groups

Cited by 55 publications

References 29 publications

Homo-Oligomerization of the Porcine Reproductive and Respiratory Syndrome Virus Nucleocapsid Protein and the Role of Disulfide Linkages

Homo-Oligomerization of the Porcine Reproductive and Respiratory Syndrome Virus Nucleocapsid Protein and the Role of Disulfide Linkages

Energies and Geometries of Isographic Hydrogen-Bonded Networks. 1. The (8) Graph Set

Molecular Mechanism of Flop Selectivity and Subsite Recognition for an AMPA Receptor Allosteric Modulator: Structures of GluA2 and GluA3 in Complexes with PEPA

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