6KEB

Structure basis for Diltiazem block of a voltage-gated calcium channel

  • Classification: TRANSPORT PROTEIN
  • Organism(s): Aliarcobacter butzleri
  • Expression System: Trichoplusia ni
  • Mutation(s): No 
  • Membrane Protein: Yes  OPMPDBTM

  • Deposited: 2019-07-04 Released: 2019-10-23 
  • Deposition Author(s): Tang, L.
  • Funding Organization(s): National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI), National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR), Howard Hughes Medical Institute

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.20 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.243 
  • R-Value Observed: 0.245 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural Basis for Diltiazem Block of a Voltage-Gated Ca2+Channel.

Tang, L.Gamal El-Din, T.M.Lenaeus, M.J.Zheng, N.Catterall, W.A.

(2019) Mol Pharmacol 96: 485-492

  • DOI: https://doi.org/10.1124/mol.119.117531
  • Primary Citation of Related Structures:  
    6KE5, 6KEB

  • PubMed Abstract: 

    Diltiazem is a widely prescribed Ca 2+ antagonist drug for cardiac arrhythmia, hypertension, and angina pectoris. Using the ancestral Ca V channel construct Ca V Ab as a molecular model for X-ray crystallographic analysis, we show here that diltiazem targets the central cavity of the voltage-gated Ca 2+ channel underneath its selectivity filter and physically blocks ion conduction. The diltiazem-binding site overlaps with the receptor site for phenylalkylamine Ca 2+ antagonist drugs such as verapamil. The dihydropyridine Ca 2+ channel blocker amlodipine binds at a distinct site and allosterically modulates the binding sites for diltiazem and Ca 2+ Our studies resolve two distinct binding poses for diltiazem in the absence and presence of amlodipine. The binding pose in the presence of amlodipine may mimic a high-affinity binding configuration induced by voltage-dependent inactivation, which is favored by dihydropyridine binding. In this binding pose, the tertiary amino group of diltiazem projects upward into the inner end of the ion selectivity filter, interacts with ion coordination Site 3 formed by the backbone carbonyls of T175, and alters binding of Ca 2+ to ion coordination Sites 1 and 2. Altogether, our results define the receptor site for diltiazem and elucidate the mechanisms for pore block and allosteric modulation by other Ca 2+ channel-blocking drugs at the atomic level. SIGNIFICANCE STATEMENT: Calcium antagonist drugs that block voltage-gated calcium channels in heart and vascular smooth muscle are widely used in the treatment of cardiovascular diseases. Our results reveal the chemical details of diltiazem binding in a blocking position in the pore of a model calcium channel and show that binding of another calcium antagonist drug alters binding of diltiazem and calcium. This structural information defines the mechanism of drug action at the atomic level and provides a molecular template for future drug discovery.


  • Organizational Affiliation

    Department of Neurology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China (L.T.); and Department of Pharmacology (L.T., T.M.G.E.-D., M.J.L., N.Z., W.A.C.), Division of General Internal Medicine, Department of Medicine (M.J.L.), and Howard Hughes Medical Institute (N.Z.), University of Washington, Seattle, Washington [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ion transport protein
A, B, C, D
284Aliarcobacter butzleriMutation(s): 0 
Membrane Entity: Yes 
UniProt
Find proteins for A8EVM5 (Aliarcobacter butzleri (strain RM4018))
Explore A8EVM5 
Go to UniProtKB:  A8EVM5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA8EVM5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PX4 (Subject of Investigation/LOI)
Query on PX4

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
J [auth B]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
J [auth B],
K [auth B],
M [auth C],
N [auth C],
O [auth C],
P [auth D],
Q [auth D],
R [auth D]
1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
C36 H73 N O8 P
CITHEXJVPOWHKC-UUWRZZSWSA-O
D6C (Subject of Investigation/LOI)
Query on D6C

Download Ideal Coordinates CCD File 
S [auth D][(2~{S},3~{R})-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxidanylidene-2,3-dihydro-1,5-benzothiazepin-3-yl] ethanoate
C22 H26 N2 O4 S
HSUGRBWQSSZJOP-SFTDATJTSA-N
CA (Subject of Investigation/LOI)
Query on CA

Download Ideal Coordinates CCD File 
I [auth B],
L [auth C]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.20 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.243 
  • R-Value Observed: 0.245 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 125.6α = 90
b = 125.63β = 90
c = 191.84γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data

  • Released Date: 2019-10-23 
  • Deposition Author(s): Tang, L.

Funding OrganizationLocationGrant Number
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesR01HL112808
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)United StatesR01NS015751
Howard Hughes Medical InstituteUnited States--

Revision History  (Full details and data files)

  • Version 1.0: 2019-10-23
    Type: Initial release
  • Version 1.1: 2022-03-23
    Changes: Author supporting evidence, Database references
  • Version 1.2: 2024-05-29
    Changes: Data collection