Proteopedia

Flaps Morph for HIV Protease

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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].

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].


  • Course-grained[4]

Wide-Open Drug-Free HIV Protease Crystal Structures[3]

PDB ID

Year

Resolution; Rfree*

Asymm. Unit

Ile50 dist.

Mutations; Comments

Wild Type

1tw7[1]

2005

1.3 Å; WTA*

2 chains

12.25 Å

I10L, N25D, V36M, L46M, V54I, V62I, P63L, V71A, A82V, V84I, M90L

3phv

2pc0

2007

1.4 Å; BTA*

1 chain

12.2 Å

K7Q

2r8n

2008

1.2 Å; A*

1 chain

12.19 Å

K7Q, I33L, R41K, I63L

Other HIV Protease Crystal Structures With Separated Flaps

4npt

2014

1.66 Å; A*

1 chain

13.2 Å

D25N; Inhibitor is between flaps

3pj6

2011

2.25 Å; U*

1 chain

11.9 Å

V10I, N25D, E35D, V36I, L46M, A82T; Structure unreliable according to Rfree.

  • Rfree is categorized by FirstGlance in Jmol as A (Average), BTA (Better Than Average), U (Unreliable), WTA (Worse Than Average) at the corresponding resolution.


  • I did not finish examining hits via google for 'hiv protease flaps animation'





  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Martin P, Vickrey JF, Proteasa G, Jimenez YL, Wawrzak Z, Winters MA, Merigan TC, Kovari LC. "Wide-open" 1.3 A structure of a multidrug-resistant HIV-1 protease as a drug target. Structure. 2005 Dec;13(12):1887-95. PMID:16338417 doi:10.1016/j.str.2005.11.005
  2. ↑ Heal JW, Jimenez-Roldan JE, Wells SA, Freedman RB, Romer RA. Inhibition of HIV-1 protease: the rigidity perspective. Bioinformatics. 2012 Feb 1;28(3):350-7. doi: 10.1093/bioinformatics/btr683. PMID:22291339 doi:http://dx.doi.org/10.1093/bioinformatics/btr683
  3. ↑ 3.0 3.1 3.2 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. OPEN ACCESS. DOI: 10.1039/C7RA09691G.
  4. ↑ Tozzini V, Trylska J, Chang CE, McCammon JA. Flap opening dynamics in HIV-1 protease explored with a coarse-grained model. J Struct Biol. 2007 Mar;157(3):606-15. doi: 10.1016/j.jsb.2006.08.005. Epub 2006 , Aug 23. PMID:17029846 doi:http://dx.doi.org/10.1016/j.jsb.2006.08.005

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