Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cryo-EM structure of K+-bound hERG channel in the presence of astemizole

ABSTRACT:

SUBMITTER: Naruhiko Adachi

PROVIDER: EMPIAR-10629 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

Cryo-EM Structure of K<sup>+</sup>-Bound hERG Channel Complexed with the Blocker Astemizole.

Asai Tatsuki T Adachi Naruhiko N Moriya Toshio T Oki Hideyuki H Maru Takamitsu T Kawasaki Masato M Suzuki Kano K Chen Sisi S Ishii Ryohei R Yonemori Kazuko K Igaki Shigeru S Yasuda Satoshi S Ogasawara Satoshi S Senda Toshiya T Murata Takeshi T

Structure (London, England : 1993) 20210114 3

The hERG channel is a voltage-gated potassium channel involved in cardiac repolarization. Off-target hERG inhibition by drugs has become a critical issue in the pharmaceutical industry. The three-dimensional structure of the hERG channel was recently reported at 3.8-Å resolution using cryogenic electron microscopy (cryo-EM). However, the drug inhibition mechanism remains unclear because of the scarce structural information regarding the drug- and potassium-bound hERG channels. In this study, we ...[more]

PMID: 33450182

Similar Datasets

Cryo-EM structure of K+-bound hERG channel

Project description: Not available

| EMPIAR-10628 | biostudies-other

Cryo-EM Structure of the Open Human Ether-a-go-go-Related K<sup>+</sup> Channel hERG.

Project description:The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure, the voltage sensors adopt a depolarized conformation, and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG's unusual sensitivity to many drugs. A subtle structural feature of the hERG selectivity filter might correlate with its fast inactivation rate, which is key to hERG's role in cardiac action potential repolarization.

| S-EPMC5484391 | biostudies-literature

Refinement of a cryo-EM structure of hERG: Bridging structure and function.

Project description:The human-ether-a-go-go-related gene (hERG) encodes the voltage-gated potassium channel (KCNH2 or Kv11.1, commonly known as hERG). This channel plays a pivotal role in the stability of phase 3 repolarization of the cardiac action potential. Although a high-resolution cryo-EM structure is available for its depolarized (open) state, the structure surprisingly did not feature many functionally important interactions established by previous biochemical and electrophysiology experiments. Using molecular dynamics flexible fitting (MDFF), we refined the structure and recovered the missing functionally relevant salt bridges in hERG in its depolarized state. We also performed electrophysiology experiments to confirm the functional relevance of a novel salt bridge predicted by our refinement protocol. Our work shows how refinement of a high-resolution cryo-EM structure helps to bridge the existing gap between the structure and function in the voltage-sensing domain (VSD) of hERG.

| S-EPMC7896098 | biostudies-literature

Cryo-EM structure of SETD2/Set2 methyltransferase bound to a nucleosome containing oncohistone mutations

Project description:Setd2 methylate the nucleosome to form H3K36me3. Here we utilized the Cryo-EM to elucidate the structure of SETD2/Set2 bound with nucleosomes. Through this structure analysis, we found that histone H1 may interfere the enzymatic activity of SETD2/Set2 by inhibiting their binding affinity.

2021-05-20 | GSE148235 | GEO

Cryo-EM structure of substrate-bound human telomerase holoenzyme.

Project description:The enzyme telomerase adds telomeric repeats to chromosome ends to balance the loss of telomeres during genome replication. Telomerase regulation has been implicated in cancer, other human diseases, and ageing, but progress towards clinical manipulation of telomerase has been hampered by the lack of structural data. Here we present the cryo-electron microscopy structure of the substrate-bound human telomerase holoenzyme at subnanometre resolution, showing two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP). In the catalytic core, RNA encircles TERT, adopting a well-ordered tertiary structure with surprisingly limited protein-RNA interactions. The H/ACA RNP lobe comprises two sets of heterotetrameric H/ACA proteins and one Cajal body protein, TCAB1, representing a pioneering structure of a large eukaryotic family of ribosome and spliceosome biogenesis factors. Our findings provide a structural framework for understanding human telomerase disease mutations and represent an important step towards telomerase-related clinical therapeutics.

| S-EPMC6223129 | biostudies-literature

Cryo-EM structure of VASH1-SVBP bound to microtubules.

Project description:The dynamic tyrosination-detyrosination cycle of α-tubulin regulates microtubule functions. Perturbation of this cycle impairs mitosis, neural physiology, and cardiomyocyte contraction. The carboxypeptidases vasohibins 1 and 2 (VASH1 and VASH2), in complex with the small vasohibin-binding protein (SVBP), mediate α-tubulin detyrosination. These enzymes detyrosinate microtubules more efficiently than soluble αβ-tubulin heterodimers. The structural basis for this substrate preference is not understood. Using cryo-electron microscopy (cryo-EM), we have determined the structure of human VASH1-SVBP bound to microtubules. The acidic C-terminal tail of α-tubulin binds to a positively charged groove near the active site of VASH1. VASH1 forms multiple additional contacts with the globular domain of α-tubulin, including contacts with a second α-tubulin in an adjacent protofilament. Simultaneous engagement of two protofilaments by VASH1 can only occur within the microtubule lattice, but not with free αβ heterodimers. These lattice-specific interactions enable preferential detyrosination of microtubules by VASH1.

| S-EPMC7449697 | biostudies-literature

Validation of cryo-EM structure of IP?R1 channel.

Project description:About a decade ago, three electron cryomicroscopy (cryo-EM) single-particle reconstructions of IP3R1 were reported at low resolution. It was disturbing that these structures bore little similarity to one another, even at the level of quaternary structure. Recently, we published an improved structure of IP3R1 at ?1 nm resolution. However, this structure did not bear any resemblance to any of the three previously published structures, leading to the question of why the structure should be considered more reliable than the original three. Here, we apply several methods, including class-average/map comparisons, tilt-pair validation, and use of multiple refinement software packages, to give strong evidence for the reliability of our recent structure. The map resolution and feature resolvability are assessed with the gold standard criterion. This approach is generally applicable to assessing the validity of cryo-EM maps of other molecular machines.

| S-EPMC3696195 | biostudies-literature

Cryo-EM structure of human heptameric Pannexin 1 channel.

Project description: Not available

| S-EPMC7196123 | biostudies-literature

Cryo-EM structure of the Spo11 core complex bound to DNA.

Project description:The DNA double-strand breaks that initiate meiotic recombination are formed by topoisomerase relative Spo11, supported by conserved auxiliary factors. Because high-resolution structural data are lacking, many questions remain about the architecture of Spo11 and its partners and how they engage with DNA. We report cryo-EM structures at up to 3.3 Å resolution of DNA-bound core complexes of Saccharomyces cerevisiae Spo11 with Rec102, Rec104, and Ski8. In these structures, monomeric core complexes make extensive contacts with the DNA backbone and with the recessed 3'-OH and first 5' overhanging nucleotide, definitively establishing the molecular determinants of DNA end-binding specificity and providing insight into DNA cleavage preferences in vivo. The structures of individual subunits and their interfaces, supported by functional data in yeast, provide insight into the role of metal ions in DNA binding and uncover unexpected structural variation in homologs of the Top6BL component of the core complex.

| S-EPMC10634984 | biostudies-literature

Cryo-EM structure of SWI/SNF complex bound to a nucleosome.

Project description:The chromatin-remodelling complex SWI/SNF is highly conserved and has critical roles in various cellular processes, including transcription and DNA-damage repair1,2. It hydrolyses ATP to remodel chromatin structure by sliding and evicting histone octamers3-8, creating DNA regions that become accessible to other essential factors. However, our mechanistic understanding of the remodelling activity is hindered by the lack of a high-resolution structure of complexes from this family. Here we report the cryo-electron microscopy structure of Saccharomyces cerevisiae SWI/SNF bound to a nucleosome, at near-atomic resolution. In the structure, the actin-related protein (Arp) module is sandwiched between the ATPase and the rest of the complex, with the Snf2 helicase-SANT associated (HSA) domain connecting all modules. The body contains an assembly scaffold composed of conserved subunits Snf12 (also known as SMARCD or BAF60), Snf5 (also known as SMARCB1, BAF47 or INI1) and an asymmetric dimer of Swi3 (also known as SMARCC, BAF155 or BAF170). Another conserved subunit, Swi1 (also known as ARID1 or BAF250), resides in the core of SWI/SNF, acting as a molecular hub. We also observed interactions between Snf5 and the histones at the acidic patch, which could serve as an anchor during active DNA translocation. Our structure enables us to map and rationalize a subset of cancer-related mutations in the human SWI/SNF complex and to propose a model for how SWI/SNF recognizes and remodels the +1 nucleosome to generate nucleosome-depleted regions during gene activation9.

| S-EPMC7319049 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data