interaction in the conformation of organic compounds. A database study

Umezawa, Yōji; Tsuboyama, Sei; Takahashi, Hiroki; Uzawa, Jun; Nishio, Motohiro

doi:10.1016/s0040-4020(99)00539-6

Cited by 245 publications

(132 citation statements)

References 68 publications

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“…The group at position C␦2, thus, appears to interact with Tyr-485 to stabilize it in the open state. The position of Leu-398 in the Kv1.2 crystal structure suggests formation of a CH-interaction (45)(46)(47) between the aromatic ring of Tyr-485 and C␦2. Neither isoleucine nor valine contain a C␦2 group and, thus, are not positioned to develop the interaction.…”

Section: Discussionmentioning

confidence: 97%

An Intersubunit Interaction between S4-S5 Linker and S6 Is Responsible for the Slow Off-gating Component in Shaker K+ Channels

Batulan¹,

Haddad

Blunck

2010

Journal of Biological Chemistry

116

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Voltage-gated ion channels are controlled by the membrane potential, which is sensed by peripheral, positively charged voltage sensors. The movement of the charged residues in the voltage sensor may be detected as gating currents. In Shaker K ؉ channels, the gating currents are asymmetric; although the on-gating currents are fast, the off-gating currents contain a slow component. This slow component is caused by a stabilization of the activated state of the voltage sensor and has been suggested to be linked to ion permeation or C-type inactivation. The molecular determinants responsible for the stabilization, however, remain unknown. Here, we identified an interaction between Arg-394, Glu-395, and Leu-398 on the C termini of the S4-S5 linker and Tyr-485 on the S6 of the neighboring subunit, which is responsible for the development of the slow off-gating component. Mutation of residues involved in this intersubunit interaction modulated the strength of the associated interaction. Impairment of the interaction still led to pore opening but did not exhibit slow gating kinetics. Development of this interaction occurs under physiological ion conduction and is correlated with pore opening. We, thus, suggest that the above residues stabilize the channel in the open state.The voltage dependence of ion channels is the basis for all electrical signaling in the central nervous system. In tetrameric voltage-gated K ϩ channels, each subunit is composed of six transmembrane ␣-helices (S1-S6), with S1-S4 forming the voltage sensing domain and S5-S6 of all four subunits forming the pore. The voltage-sensing domains are covalently connected to the S5 of the pore region by the S4-S5 linker. The intracellular gate is made up of the S6 C-terminal ends that cross each other, forming a bundle that occludes the pore when the channel is closed. Pore opening in voltage-gated K ϩ channels is controlled by the movement of the voltage sensor in which charged residues of the S4 respond to changes in membrane potential. During this conformational change, the charges are moved through the electric field, generating the transient gating currents (for review, see Ref. 1). Gating currents were first predicted by Hodgkin and Huxley and were first detected in sodium channels by Armstrong et al. (2, 3). The movement is transferred to the pore domain (electromechanical coupling) and subsequently leads to pore opening. Voltage sensor movement precedes pore opening so that the transitions the channel undergoes during electromechanical coupling are reflected in the gating currents.Activation (on) and deactivation (off) gating currents for the non-conducting Shaker-IR channel, W434F (4 -6) have been previously described (6 -8). Briefly, on-gating currents rise and decay quickly after small depolarizations but rise more slowly and exhibit more prolonged and complex decay kinetics after intermediate depolarizations and, finally, develop and decay rapidly after depolarizations large enough to activate all channels. In contrast, offgating currents, which de...

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Section: Discussionmentioning

confidence: 97%

An Intersubunit Interaction between S4-S5 Linker and S6 Is Responsible for the Slow Off-gating Component in Shaker K+ Channels

Batulan¹,

Haddad

Blunck

2010

Journal of Biological Chemistry

116

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“…3b, that the structure consists mainly of turns and loops. In Zn 4 SmtA, a CH͞ interaction (33) between H(␣) of Ala-37, part of the ␣-helix, and the aromatic ring of Tyr-31, part of the ␤-sheet, provides direct communication between the two secondary structure elements (Fig. 4a), and accounts for the remarkable high-field shift of the H(␣) proton of Ala-37 (1.73 ppm; induced by the ring current of Tyr-31).…”

Section: Methodsmentioning

confidence: 99%

A metallothionein containing a zinc finger within a four-metal cluster protects a bacterium from zinc toxicity

Blindauer

Harrison

Parkinson

et al. 2001

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

172

183

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Zinc is essential for many cellular processes, including DNA synthesis, transcription, and translation, but excess can be toxic. A zinc-induced gene, smtA, is required for normal zinc-tolerance in the cyanobacterium Synechococcus PCC 7942. Here we report that the protein SmtA contains a cleft lined with Cys-sulfur and His-imidazole ligands that binds four zinc ions in a Zn4Cys9His2 cluster. The thiolate sulfurs of five Cys ligands provide bridges between the two ZnCys 4 and two ZnCys3His sites, giving two fused six-membered rings with distorted boat conformations. The inorganic core strongly resembles the Zn4Cys11 cluster of mammalian metallothionein, despite different amino acid sequences, a different linear order of the ligands, and presence of histidine ligands. Also, SmtA contains elements of secondary structure not found in metallothioneins. One of the two Cys4-coordinated zinc ions in SmtA readily exchanges with exogenous metal ( 111 Cd), whereas the other is inert. The thiolate sulfur ligands bound to zinc in this site are buried within the protein.Regions of ␤-strand and ␣-helix surround the inert site to form a zinc finger resembling the zinc fingers in GATA and LIM-domain proteins. Eukaryotic zinc fingers interact specifically with other proteins or DNA and an analogous interaction can therefore be anticipated for prokaryotic zinc fingers. SmtA now provides structural proof for the existence of zinc fingers in prokaryotes, and sequences related to the zinc finger motif can be identified in several bacterial genomes.

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“…As multiple C-H/π interactions formed between side chains can be significant, they may be considered as one of the driving forces to constrain a peptide conformation and consequently direct specific conformation in many proteins [156]. Using the crystal structure database Nishio et al investigated the C-H/π interactions in peptides [157,158]. Evidence to indicate that 42% of the structures studied exhibited such aromatic interactions was found.…”

Section: C-h/π Hydrogen Bondsmentioning

confidence: 99%

“…The effect of substituents is a useful probe for the hydrogen bond character of C-H/π interactions, as in the formate ester 23 ( Figure 7) since, if it behaves like a conventional hydrogen bond, an electron donating substituent on the hydrogen bond acceptor should increase the interaction. From peptide studies it was found that C-H/π interactions are favored in 5-and 6-membered rings, and this prompted a further study of a series of organic molecules capable of forming 5-, 6-and 7-membered ring C-H/π interactions ( Figure 8) [166,157,168]. Electron donating substituents on the aromatic ring should raise the energy of the highest occupied π-orbital, and electron withdrawing substituents on the carbon atom of the C-H donor should lower the C-H antibonding orbital and hence the energy gap of the interacting orbitals required for a C-H/π hydrogen bond, thus making the interaction favorable.…”

Section: Intramolecular C-h/π Interactions and The Conformation Of Ormentioning

confidence: 99%

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

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The effect of weak intermolecular interactions on the binding affinity between ligand-protein complexes plays an important role in stabilizing a ligand at the interface of a protein structure. In this review article, we will explore the different ways of taking into account these interactions, mainly intramolecular hydrogen bonds, in docking calculations. Their possible limitations and their suitable application domains are highlighted. Inspection of the outliers of this study probed very stimulating, as it provides opportunities and inspiration to medicinal chemists, being a reminder of the impact that minimal chemical modifications can have on biological activities.

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interaction in the conformation of organic compounds. A database study

Cited by 245 publications

References 68 publications

An Intersubunit Interaction between S4-S5 Linker and S6 Is Responsible for the Slow Off-gating Component in Shaker K+ Channels

An Intersubunit Interaction between S4-S5 Linker and S6 Is Responsible for the Slow Off-gating Component in Shaker K+ Channels

A metallothionein containing a zinc finger within a four-metal cluster protects a bacterium from zinc toxicity

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

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