9p24 | pdb_00009p24

Structure of human cardiac sodium channel Nav1.5 in intermediate open state

spinqualitylabelsall models 9p24, resolution 3.48Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9p24 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.48Å Ligands: 9Z9, NA, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SCN5A_HUMAN Defects in SCN5A are a cause of progressive familial heart block type 1A (PFHB1A) [MIM:113900; also known as Lenegre-Lev disease or progressive cardiac conduction defect (PCCD). PFHB1A is an autosomal dominant cardiac bundle branch disorder that may progress to complete heart block. PFHB1A is characterized by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, leading to complete atrioventricular block and causing syncope and sudden death. Defects in SCN5A are the cause of long QT syndrome type 3 (LQT3) [MIM:603830. Long QT syndromes are heart disorders characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress. LQT3 inheritance is an autosomal dominant. [:] Defects in SCN5A are the cause of Brugada syndrome type 1 (BRGDA1) [MIM:601144. An autosomal dominant tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset. Defects in SCN5A are the cause of sick sinus syndrome type 1 (SSS1) [MIM:608567. The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors, in which case it is considered to be a congenital disorder. Defects in SCN5A are the cause of familial paroxysmal ventricular fibrillation type 1 (VF1) [MIM:603829. A cardiac arrhythmia marked by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricle and by absence of atrial activity. Defects in SCN5A may be a cause of sudden infant death syndrome (SIDS) [MIM:272120. SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. Long QT syndromes-associated mutations can be responsible for some of SIDS cases. Defects in SCN5A may be a cause of familial atrial standstill (FAS) [MIM:108770. Atrial standstill is an extremely rare arrhythmia, characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm. Defects in SCN5A are the cause of cardiomyopathy dilated type 1E (CMD1E) [MIM:601154; also known as dilated cardiomyopathy with conduction disorder and arrhythmia or dilated cardiomyopathy with conduction defect 2. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. Defects in SCN5A are the cause of familial atrial fibrillation type 10 (ATFB10) [MIM:614022. ATFB10 is a familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. Function SCN5A_HUMAN This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels. Publication Abstract from PubMed Voltage-gated sodium channels are vital for regulating excitability in muscle and nerve cells, and their dysregulation is linked to a range of diseases. However, therapeutic targeting of Na(v) channels remains challenging due to a limited understanding of their gating mechanisms. Here, we present a cryo-EM structure of human Na(v)1.5 in an intermediate open state, stabilized by interactions between the N-terminal domain and the S6(I) segment. This structure reveals a possible Na(+) binding site adjacent to the conserved inactivation (IFM) motif. Molecular dynamics simulations demonstrate that monovalent cations stably occupy this site, while electrophysiological recordings demonstrate that ion binding modulates IFM motif docking and fast inactivation kinetics. Our findings reveal that IFM accessibility is dynamically regulated in this intermediate state, refining the canonical door-wedge model of fast inactivation. Collectively, our study provides a revised structural framework for Na(v)1.5 gating mechanisms, suggesting an alternative pathway for ion accessibility that may inform better mechanistic and therapeutic strategies for treating Na(v)1.5-related cardiac arrhythmias. Structural and functional mechanisms underlying activation gate dynamics and IFM motif accessibility in human Na(v)1.5.,Biswas R, Lopez-Serrano AL, Purohit A, Ramirez-Navarro A, Huang HL, Cheng X, Heissler SM, Deschenes I, Chinthalapudi K Nat Commun. 2026 Feb 16;17(1):2820. doi: 10.1038/s41467-026-69672-x. PMID:41698958 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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