4G28

Calcium-calmodulin complexed with the calmodulin binding domain from a small conductance potassium channel splice variant and EBIO-1

Summary for 4G28

• Entry DOI: 10.2210/pdb4g28/pdb
• Related: 1G4Y 3SJQ 4G27
• Descriptor: Small conductance calcium-activated potassium channel protein 2, Calmodulin, SULFATE ION, ... (7 entities in total)
• Functional Keywords: protein-protein complex, ef hand, metal binding protein, metal transport-calcium binding protein complex, metal transport/calcium binding protein
• Biological source: Rattus norvegicus (rat); More
• Cellular location: Membrane; Multi-pass membrane protein: P70604
• Total number of polymer chains: 2
• Total formula weight: 29718.57

Authors

Zhang, M.,Pascal, J.M.,Zhang, J.-F. (deposition date: 2012-07-11, release date: 2012-09-12, Last modification date: 2024-02-28)

Primary citation

Zhang, M.,Pascal, J.M.,Schumann, M.,Armen, R.S.,Zhang, J.F.
Identification of the functional binding pocket for compounds targeting small-conductance Ca(2+)-activated potassium channels.
Nat Commun, 3:1021-1021, 2012

PubMed Abstract: Small- and intermediate-conductance Ca(2+)-activated potassium channels, activated by Ca(2+)-bound calmodulin, have an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potential for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-ethyl-2-benzimidazolinone (1-EBIO) class is located at the calmodulin-channel interface. We show that, based on structure data and molecular docking, mutations of the channel can effectively change the potency of these compounds. Our results provide insight into the molecular nature of the binding pocket and its contribution to the potency and selectivity of the compounds of the 1-EBIO class.

PubMed: 22929778
DOI: 10.1038/ncomms2017

Experimental method

X-RAY DIFFRACTION (1.63 Å)