Drug resistance P-Glycoprotein // Drug Repurposing

Drug resistance P-Glycoprotein

A research team from the Scripps Research Institute and the Texas Tech University Health Sciences Center has obtained the first glimpse of a protein that keeps certain substances, including many drugs, out of cells. The protein, called P-glycoprotein, or P-gp for short, is one of the main reasons cancer cells are resistant to chemotherapy drugs. Understanding its structure may help scientists design more effective drugs. The structure is a nice tool for understanding how drugs are transported out of cells by P-gp and for designing drugs to evade P-gp, preventing drug resistance.

P-gp structure. Six transmembrane helices (TMs) and two nucleotide-binding domains (NBDs) are labeled and numbered. The two halves of the molecule (N- and C-terminal halves) are colored yellow and blue, respectively.

P-gp, a protein first identified in 1976, sits in the membrane that surrounds human cells, including those in the gut, intestine, kidney, and brain, where it functions as a gate keeper, shooing out potentially harmful agents. Problematically, P-gp not only transports substances that are harmful out of the cell, but also drugs targeted to cancer cells and HIV-infected cells, as well as some therapeutics aimed at alleviating psychiatric conditions.

The scientists succeeded in performing the x-ray crystallography on mouse protein P-gp at SSRL, APS, and ALS Beamlines 8.2.2 and 8.3.1. Once they solved the structure, they found that the mouse P-gp, which is 87 percent identical to its human counterpart, has the shape of an upside down "V" or an inverted cone with a large cavity inside. The cone's interior is lined with amino acids that bind to various substances, holding them in place. The top part of the cone resides inside the cell membrane and has two openings for substances to enter; the bottom portion protrudes into the cell, ending in two dumbbell-shaped arms.

This overall shape is strikingly similar to that of another protein, MsbA, that transports lipids out of bacteria (see previous ALS highlight, "Protein Flips Lipids Across Membranes"). This similarity suggests that P-gp works by bringing the two dumbbell-shaped arms together on the inside of the cell and opening the closed end toward the outside of the cell, essentially reversing direction of the "v" shape so any substance caught inside the protein's cavity is ejected from the cell.

Model of substrate direct transport by P-gp (gray). (a) Substrate molecules (magenta) enter a cavity lined with amino acids (cyan) that bind to a wide variety of molecules. (b) ATP molecules (yellow)...


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Sickle cell

by coelentrate

Sickle cell is not the best example I gave. The best examples are lactose tolerance in humans and evolution of drug resistance in microbes because these are physical changes that humans have observed with their own eyes.
sickle cell is also circumstantial evidence. we think that the sickle cell allele should have dissapeared but it dsidn't. we guess it's malaria resistance. And we guess the reason is selective pressure.

Hard to say.

by pleni

Since bacteria don't fossilize, it is hard to determine what transitions have occurred. Here is a little bit of info on it. The interesting thing about bacteria is that one generation is very short compared to human generations. That is why we can see evolution happening in "real time" in bacteria, but can't see it in humans or other animals.
"Antibacterial resistance is an example of evolution in action. Whenever an antibiotic is used, there is always the chance that some of the bacteria will survive. Compared to the bacteria that were killed off, the survivors have genes that make them more resistant to the drug

Humana Press Multi-Drug Resistance in Cancer (Methods in Molecular Biology)
Book (Humana Press)

Awards presented at Hoyle School  — spectator.southcoasttoday
He noted that Lt. Cabral served as the Drug Awareness Resistance Education (DARE) officer for three years without being paid after the town went through a difficult financial time.

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