Multidrug resistance in biology and medicine - the human MDR1 P-glycoprotein
The human P-glycoprotein (P-gp) is a member of a large family of evolutionarily conserved membrane transporters called the ABC-transporters.
These proteins are used to move many different types of substances across cell membranes.
Human P-gp has caused many problems in the medical treatment of cancers and viral infections like HIV-AIDS because this transporter is able to "pump" chemotherapeutic drugs out of the cell.
P-gp is also able to bind many different drugs, which compounds the problem. Cells expressing P-gp or over-expressing P-gp become resistant to the effects of many different drugs because of its ability to "pump them overboard".
See below for an introduction to our current studies on this fascinating enzyme.
Important remaining questions about how P-gp functions:
What is the 3-dimensional structure of human P-gp?
In order to understand how the transporter works, we need to know what it looks like.
Before we can attempt to fix the medical problems associated with P-gp, we need to know how it works.
How can we inhibit this Multidrug Resistance transporter?
If we can find a compound that inhibits the pump, we may be able to use it as part of the treatment with the chemotherapeutics.
Knocking out the pump may then destroy the drug resistance so the chemotherapy works again.
What is the structure of P-gp?
Evolutionarily related proteins from bacteria are known that are closely related to the human P-gp by their protein sequences. Some of these bacterial proteins have known 3-dimensional structures.
Above: The related multidrug resistance pump from
Staphylococcus aureus SAV1866 (from DAWSON, R. J. P. & LOCHER,
Structure of a bacterial multidrug ABC transporter. Nature, 443, 180-5).
This pump shares a strong evolutionary relationship with P-gp (34% identity and 53% conservative substitutions).
Structure based on homology:
Even though no structure has yet been determined for the human P-gp, because it is so related to the other members of the ABC family, we are able to infer a structure. This process is called homology modeling.
Above: A 3-dimensional model of P-gp based on the SAV1866
This initial model was calculated by using the backbone positions of the Staphylococcus aureus enzyme
and solving a best fit to the amino acid side chains using a computational technique known as simulated annealing.
Computer simulation of the membrane environment
Above: Human P-pg in a phospholipid membrane.
This allows us to simulate in our computing cluster the interactions that P-gp has in its transmembrane regions.
Computer simulation in the aqueous environment
Above: Human P-pg in a phospholipid membrane
with an added box of water.
This allows us to simulate the rest of the interactions that P-gp has in its aqueous environments.
In silico docking of drug molecules to the 3-D structure
3-D homology model of human P-gp with the anti-cancer drug, vinblastine, bound.
Current research directions:
We are currently studying how the P-gp binds various drugs and are search for novel compounds that may function as inhibitors.
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