Flaps Morph for HIV Protease: Difference between revisions
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The proteolytic active site of HIV protease is [[Immunodeficiency virus protease|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<ref>PMID:22291339</ref>. Mutations in HIV protease that confer resistance to inhibitor drugs often involve changes to the flaps<ref name="wide-open" />. The ''active site expansion'' hypothesis states that mutations responsible for multi-drug resistance expand the active site cavity, thereby reducing drug affinity<ref name="wide-open" />. | The proteolytic active site of HIV protease is [[Immunodeficiency virus protease|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<ref>PMID:22291339</ref>. Mutations in HIV protease that confer resistance to inhibitor drugs often involve changes to the flaps<ref name="wide-open" />. The ''active site expansion'' hypothesis states that mutations responsible for multi-drug resistance expand the active site cavity, thereby reducing drug affinity<ref name="wide-open" />. | ||
There are [[Immunodeficiency virus protease 3D structures|hundreds of HIV protease crystal structures]]. When crystallized with bound inhibitor, the flaps have always been closed<ref name="processes" />. Inhibitor-free crystal structures have been classified into '''closed, semi-open,''' and '''wide open'''<ref name="processes" />. 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<ref name="wide-open" />. | There are [[Immunodeficiency virus protease 3D structures|hundreds of HIV protease crystal structures]]. When crystallized with bound inhibitor, the flaps have always been closed<ref name="processes">Yu, Y. ''et al.'', Structural insights into HIV-1 protease flap opening processes and key intermediates. 2017 RSC Advances, '''7''':45121-8. '''NOT IN PUBMED.''' [https://pubs.rsc.org/en/content/articlehtml/2017/ra/c7ra09691g OPEN ACCESS]. DOI: [https://doi.org/10.1039/C7RA09691G 10.1039/C7RA09691G].</ref>. Inhibitor-free crystal structures have been classified into '''closed, semi-open,''' and '''wide open'''<ref name="processes" />. 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<ref name="wide-open" />. | ||
In the case of mutant [[1tw7]], about 100 water molecules reside in the active site, forming a hydrogen-bonded scaffold holding the flaps open<ref name="wide-open" />. | In the case of mutant [[1tw7]], about 100 water molecules reside in the active site, forming a hydrogen-bonded scaffold holding the flaps open<ref name="wide-open" />. | ||
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*Course-grained<ref>PMID:17029846 </ref> | *Course-grained<ref>PMID:17029846 </ref> | ||
<table class="wikitable" style="text-align:center;"> | <table class="wikitable" style="text-align:center;"> | ||