ArticleThe Journal of biological chemistry2009
Structural model for dihydropyridine binding to L-type calcium channels.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 84 citations in OpenAlex.
- Role of Dyadic Proteins in Proper Heart Function and Disease.International journal of molecular sciences · 2025Review
- Chemical and Genetic Validation of an Essential Calcium Entry Channel ofACS infectious diseases · 2025Article
- Mechanisms of dihydropyridine agonists and antagonists in view of cryo-EM structures of calcium and sodium channels.The Journal of general physiology · 2023Article
- AlClRSC advances · 2023Article
- Modulation of L-type calcium channels in Alzheimer's disease: A potential therapeutic target.Computational and structural biotechnology journal · 2023Review
- Acetaminophen treatment evokes anticontractile effects in rat aorta by blocking L-type calcium channels.Pharmacological reports : PR · 2022Article
- P-Loop Channels: Experimental Structures, and Physics-Based and Neural Networks-Based Models.Membranes · 2022Review
- Role of High Voltage-Gated CaCells · 2021Review
- Investigation of the Selectivity of L-Type Voltage-Gated Calcium Channels 1.3 for Pyrimidine-2,4,6-Triones Derivatives Based on Molecular Dynamics Simulation.Molecules (Basel, Switzerland) · 2020Article
- Phenylalkylamines in calcium channels: computational analysis of experimental structures.Journal of computer-aided molecular design · 2020Article
- Ritanserin blocks CaActa pharmacologica Sinica · 2020Article
- Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2020Article
- 4-Pyridinio-1,4-Dihydropyridines as Calcium Ion Transport Modulators: Antagonist, Agonist, and Dual Action.Oxidative medicine and cellular longevity · 2020Article
- Lercanidipine Synergistically Enhances Bortezomib Cytotoxicity in Cancer Cells via Enhanced Endoplasmic Reticulum Stress and Mitochondrial CaInternational journal of molecular sciences · 2019Article
- Roles and Regulation of Voltage-gated Calcium Channels in Arrhythmias.The Journal of innovations in cardiac rhythm management · 2019Review
- Molecular Determinants of the Differential Modulation of CaMolecular pharmacology · 2018Article
- Unveiling (-)-Englerin A as a Modulator of L-Type Calcium Channels.Angewandte Chemie (International ed. in English) · 2016Article
- Article
- 1,4-Dihydropyridine Derivatives: Dihydronicotinamide Analogues-Model Compounds Targeting Oxidative Stress.Oxidative medicine and cellular longevity · 2016Review
- Functional, electrophysiological and molecular docking analysis of the modulation of Cav 1.2 channels in rat vascular myocytes by murrayafoline A.British journal of pharmacology · 2016Article
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
1,4-Dihydropyridines (DHPs) constitute a major class of ligands for L-type Ca(2+) channels (LTCC). The DHPs have a boat-like, six-membered ring with an NH group at the stern, an aromatic moiety at the bow, and substituents at the port and starboard sides. Various DHPs exhibit antagonistic or agonistic activities, which were previously explained as stabilization or destabilization, respectively, of the closed activation gate by the portside substituents. Here we report a novel structural model in which agonist and antagonist activities are determined by different parts of the DHP molecule and have different mechanisms. In our model, which is based on Monte Carlo minimizations of DHP-LTCC complexes, the DHP moieties at the stern, bow, and starboard form H-bonds with side chains of the key DHP-sensing residues Tyr_IIIS6, Tyr_IVS6, and Gln_IIIS5, respectively. We propose that these H-bonds, which are common for agonists and antagonists, stabilize the LTCC conformation with the open activation gate. This explains why both agonists and antagonists increase probability of the long lasting channel openings and why even partial disruption of the contacts eliminates the agonistic action. In our model, the portside approaches the selectivity filter. Hydrophobic portside of antagonists may induce long lasting channel closings by destabilizing Ca(2+) binding to the selectivity filter glutamates. Agonists have either hydrophilic substituents or a hydrogen atom at their portside, and thus lack this destabilizing effect. The predicted orientation of the DHP core allows accommodation of long substituents in the domain interface or in the inner pore. Our model may be useful for developing novel clinically relevant LTCC blockers.
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