Structural model for phenylalkylamine binding to L-type calcium channels

J Biol Chem. 2009 Oct 9;284(41):28332-42. doi: 10.1074/jbc.M109.027326. Epub 2009 Aug 21.


Phenylalkylamines (PAAs), a major class of L-type calcium channel (LTCC) blockers, have two aromatic rings connected by a flexible chain with a nitrile substituent. Structural aspects of ligand-channel interactions remain unclear. We have built a KvAP-based model of LTCC and used Monte Carlo energy minimizations to dock devapamil, verapamil, gallopamil, and other PAAs. The PAA-LTCC models have the following common features: (i) the meta-methoxy group in ring A, which is proximal to the nitrile group, accepts an H-bond from a PAA-sensing Tyr_IIIS6; (ii) the meta-methoxy group in ring B accepts an H-bond from a PAA-sensing Tyr_IVS6; (iii) the ammonium group is stabilized at the focus of P-helices; and (iv) the nitrile group binds to a Ca(2+) ion coordinated by the selectivity filter glutamates in repeats III and IV. The latter feature can explain Ca(2+) potentiation of PAA action and the presence of an electronegative atom at a similar position of potent PAA analogs. Tyr substitution of a Thr in IIIS5 is known to enhance action of devapamil and verapamil. Our models predict that the para-methoxy group in ring A of devapamil and verapamil accepts an H-bond from this engineered Tyr. The model explains structure-activity relationships of PAAs, effects of LTCC mutations on PAA potency, data on PAA access to LTCC, and Ca(2+) potentiation of PAA action. Common and class-specific aspects of action of PAAs, dihydropyridines, and benzothiazepines are discussed in view of the repeat interface concept.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Calcium Channel Blockers* / chemistry
  • Calcium Channel Blockers* / metabolism
  • Calcium Channels, L-Type / chemistry*
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Computer Simulation
  • Dihydropyridines / chemistry
  • Gallopamil / chemistry
  • Gallopamil / metabolism
  • Models, Molecular*
  • Molecular Sequence Data
  • Molecular Structure
  • Monte Carlo Method
  • Protein Structure, Tertiary*
  • Sequence Alignment
  • Structure-Activity Relationship
  • Verapamil / analogs & derivatives
  • Verapamil / chemistry
  • Verapamil / metabolism


  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Dihydropyridines
  • Gallopamil
  • Verapamil
  • devapamil