PDBsum entry 4g27

Metal transport/calcium binding protein

PDB id: 4g27

Contents

Protein chains

87 a.a.

146 a.a.

Ligands

SO4 ×3

GOL

PHU

Metals

_CA ×2

Waters ×208

PDB id:

4g27

Name:

Metal transport/calcium binding protein

Title:

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

Structure:

Small conductance calcium-activated potassium channel protein 2. Chain: b. Fragment: calmodulin binding domain (unp residues 396-487). Synonym: small conductance potassium channel splice variant, sk2a, sk2, skca 2, skca2, kca2.2. Engineered: yes. Calmodulin. Chain: r.

Source:

Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: kcnn2. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: calm1, calm, cam, cam1, calm2, cam2, camb, calm3, cam3, camc. Expression_system_taxid: 562

Resolution:

1.65Å R-factor: 0.193 R-free: 0.228

Authors:

M.Zhang,J.M.Pascal,J.-F.Zhang

Key ref:

M.Zhang et al. (2012). Identification of the functional binding pocket for compounds targeting small-conductance Ca²⁺-activated potassium channels. Nat Commun, 3, 1021. PubMed id: 22929778

Date:

11-Jul-12 Release date: 12-Sep-12

Protein chain

P70604  (KCNN2_RAT) -  Small conductance calcium-activated potassium channel protein 2 from Rattus norvegicus

Seq: 580 a.a.

Struc: 87 a.a.*

Protein chain

P0DP29  (CALM1_RAT) -  Calmodulin-1 from Rattus norvegicus

Seq: 149 a.a.

Struc: 146 a.a.

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Nat Commun 3:1021 (2012)

PubMed id: 22929778

Identification of the functional binding pocket for compounds targeting small-conductance Ca²⁺-activated potassium channels.

M.Zhang, J.M.Pascal, M.Schumann, R.S.Armen, J.F.Zhang.

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.