P-Glycoprotein
Tesi Campia su MDR

DEFINITION

P-glycoprotein (P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins. 1989)

• Glycoprotein with a molecular weight approximately of 170 kDa;
• Produced by the mdr-1 gene (Characterization of the human MDR1 gene. 2005).

Wikigenes

OMIM

CHEMICAL STRUCTURE AND IMAGES

Structure of P-Glycoprotein (Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. 2009)

The first crystal structure of a mammalian P-glycoprotein

Biochemical stucture of Pgp

Pgp is composed by:

• a transmembrane domain (TMD), the main site for drug’s interaction (The transmembrane domains of the human multidrug resistance P-glycoprotein are sufficient to mediate drug binding and trafficking to the cell surface. 1999);
• a binding domain with ATP (NBD= nucleotide-binding domain o ABS=ATP- binding site) (Functional role of the linker region in purified human P-glycoprotein. 2009);
• three intracellular hydrophilic C-terminal (ICD) that link TMD to NBD and they are divided in ICD1, ICD2 and ICD3.

Protein Aminoacids Percentage

CELLULAR FUNCTIONS

- Eject out of cells a large variety of cytotoxic substances using energy derived by ATP-hydrolysis;
- This protein is present in healty cells (Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. 1987) and it is upregulated within tumor cells of individuals with increased resistance to chemiotherapy treatment (Expression of multidrug resistance proteins in prostate cancer is related with cell sensitivity to chemotherapeutic drugs. 2009";
- Pgp substrates include cytotoxic agents, the anthracyclines,the Vinca alkaloids, the taxanes and epipodofilotoxins and among the new antitumoral drugs, Imatinib (Functional consequence of MDR1 expression on Imatinib intracellular concentrations. 2003) and Gemtuzumab (Multidrug-resistance phenotype and clinical responses to Gentuzumab ozogamicin. 2001).
The anthracyclines (eg doxorubicin, daunorubicin and epirubicin) are some of the drugs most frequently used in the treatment of tumors (Analysis of drug transport kinetics in multidrug-resistant cells: implications for drug action. 2001).

Function of P-Glycoprotein
This transmembrane protein forms a pore to remove drug from the cell with an ATP-dependent mechanism. The energy is obtained by ATP hydrolysis; the binding of substrate to C-terminal stimulates the hydolysis of ATP into ADP + Pi that induce a Pgp conformational change resulting in a decrease of affinity for the substrate, which is tranferred first to the N-terminal site and then released outside the cell (The power of the pump: mechanisms of action of P-glycoprotein (ABCB1). 2006).