Creative Bioarray Release Validated Preclinical Models to Support All Stages of Drug Discovery

The human body voltage-induced K + channel hERG plays a basic role in the repolarization of cardiac action potentials and can effectively control the QT interval of the ECG. The recent open-channel cryo-EM structure of hERG should greatly promote the understanding of the molecular basis of hERG channel diseases and drug-induced LQTS. This cardiac function of hERG is the characteristic of its unique gating characteristics: like other voltage-sensitive K + channels, hERG opens due to the voltage-dependent response of its voltage sensor domain after membrane depolarization; however, the channel is almost immediately deactivated, restricting K+ passage until the AP repolarization phase begins. In addition to rapid onset and recovery from inactivation, hERG will also be inactivated very slowly. Therefore, even if the membrane potential returns to the resting potential, an outward K + current will flow. This strongly supports the effective repolarization of cardiac AP.

At least as important as its role in hERG-related congenital arrhythmias, the pharmacological sensitivity of hERG is blocked by a variety of drugs with diverse functions and structures, which is the basis of the drug-induced acquired LQTS form. The potential of hERG to participate in drug-related arrhythmias is so strong that existing preclinical guidelines require hERG block testing for all new drugs, usually using hERG analysis. Understanding the molecular basis of hERG hybrid drug blocking will help to pre-screen the responsibilities of drugs for hERG in drug development plans and reduce the adverse effects on other useful drugs through targeted chemical modifications. Similarly, an in-depth understanding of the molecular basis of the abnormal gating characteristics of hERG, especially the mechanism of rapid onset and recovery from inactivation, and the disturbance of inactivation by congenital short QT mutations, should greatly promote the development of SQTS therapeutic interventions.

In order to understand the molecular basis of hERG's unique gating dynamics and its sensitivity to pharmacological inhibition, great efforts have been made. In the case of long-term lack of hERG structure, many functional data of wild-type hERG and channel mutants have been explained using the homology model of the channel. In view of this, the latest cryo-electromagnetic structure of hERG is very popular, and it has the potential to promote significant progress in understanding the molecular basis of hERG drug block and hERG channel gating.

In addition to drug blocker sensitivity, hERG is also activated by a series of molecules that can increase K + conductance or slow down channel inactivation by reducing inactivation and/or shifting its voltage-dependently to depolarization potential (or Some combination of these effects) to work. hERG activators are expected to treat heart disease involving hERG dysfunction, such as a subset of cases of long QT syndrome, which are caused by dysfunction of mutant channels trafficked to the plasma membrane.

Although it is expected that hERG should be inactivated to a large extent, the channel may have been captured in the pre-inactivated open state. Although this complicates the understanding of the way high-affinity drugs interact with channels (because some of them require conformational changes related to "inactivation" to achieve maximum binding affinity), it suggests that the structure may be A good template for optimizing drug interactions.

The hERG activator category is designed to inhibit inactivation by combining and stabilizing the open state of pre-inactivation. hERG and rEAG structures should also be useful templates for molecular dynamics (MD) simulations to explore the local structure and dynamic effects of natural mutations that affect gating, as well as conformational changes, which involve the reconfiguration of S5, hole and turret spiral KCNH series Gated. As usual, hope for more structural information, and the wish list will include hERG structures complexed with high-affinity blockers, deactivated activators, and structures stuck in an inactive (rest) state. At present, the cryoEM structure of hERG provides a fascinating structural environment for exploring and interpreting a large amount of experimental data about this important biophysical and pharmacological pathway.

https://www.creative-bioarray.com/acroscell/herg-ikr-kv11-1.html

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