3G61

Structure of P-glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding

3G61 の概要

• エントリーDOI: 10.2210/pdb3g61/pdb
• 関連するPDBエントリー: 3G5U 3G60
• 分子名称: Multidrug resistance protein 1a, (4S,11S,18S)-4,11,18-tri(propan-2-yl)-6,13,20-triselena-3,10,17,22,23,24-hexaazatetracyclo[17.2.1.1~5,8~.1~12,15~]tetracosa-1(21),5(24),7,12(23),14,19(22)-hexaene-2,9,16-trione (2 entities in total)
• 機能のキーワード: p-glycoprotein, pgp, multidrug resistance, membrane protein, cycle peptides, atp-binding, nucleotide-binding
• 由来する生物種: Mus musculus (mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 286545.46

構造登録者

Aller, S.G.,Yu, J.,Ward, A.,Weng, Y.,Chittaboina, S.,Zhuo, R.,Harrell, P.M.,Trinh, Y.T.,Zhang, Q.,Urbatsch, I.L.,Chang, G. (登録日: 2009-02-05, 公開日: 2009-03-24, 最終更新日: 2024-02-21)

主引用文献

Aller, S.G.,Yu, J.,Ward, A.,Weng, Y.,Chittaboina, S.,Zhuo, R.,Harrell, P.M.,Trinh, Y.T.,Zhang, Q.,Urbatsch, I.L.,Chang, G.
Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding.
Science, 323:1718-1722, 2009

PubMed Abstract: P-glycoprotein (P-gp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance (MDR) in the treatment of cancers. Substrate promiscuity is a hallmark of P-gp activity, thus a structural description of poly-specific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo P-gp at 3.8 angstroms reveals an internal cavity of approximately 6000 angstroms cubed with a 30 angstrom separation of the two nucleotide-binding domains. Two additional P-gp structures with cyclic peptide inhibitors demonstrate distinct drug-binding sites in the internal cavity capable of stereoselectivity that is based on hydrophobic and aromatic interactions. Apo and drug-bound P-gp structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding.

PubMed: 19325113
DOI: 10.1126/science.1168750

実験手法

X-RAY DIFFRACTION (4.35 Å)