Flaps Morph for HIV Protease

The genome of HIV codes for synthesis of a polyprotein (UniProt P04585 (POL_HV1H2)) that requires cutting by HIV protease in order to be separated into individual mature proteins required for virus maturation^[1]. Drugs that inhibit HIV protease prevent the virus from replicating, and are crucial components of anti-HIV therapies.

The proteolytic active site of HIV protease is covered by two "flaps". It is believed that these flaps must open to enable substrate polyprotein to enter the active site. Drugs that inhibit HIV protease tend to "lock" the flaps closed^[2]. Mutations in HIV protease that confer resistance to inhibitor drugs often involve changes to the flaps^[1]. The active site expansion hypothesis states that mutations responsible for multi-drug resistance expand the active site cavity, thereby reducing drug affinity^[1].

There are hundreds of HIV protease crystal structures. When crystallized with bound inhibitor, the flaps have nearly always been closed^[3]. Inhibitor-free crystal structures have been classified into closed, semi-open, and wide open^[3]. As of 2017, no crystal structure has captured a fully open conformation, defined as a distance of >13 Å between isoleucine 50's at the tips of the flaps^[1].

Here is shown a morph between a closed HIV protease and a "wide open" protease (). (Note that "wide open" is not "fully open" -- see above.)

In the case of mutant 1tw7, about 100 water molecules reside in the active site, forming a hydrogen-bonded scaffold holding the flaps open^[1].