Flaps Morph for HIV Protease

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HIV protease: morph of flaps opening/closing (1hxw1tw7).

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Flaps in Other Proteins

These were found by searching for "flaps" in Proteopedia.

Methods

1hxw, containing the inhibitor Ritonavir, was selected in part because it is more closed than an early, unliganded wild type structure: Ile50 to Gly27 is 11.6 Å in 1hxw, vs. 16.9 Å in 3phv. (The only mutation in 1hxw is S37N.) 1tw7, with "wide open" flaps, was selected in part because its asymmetric unit contains two chains. It has many drug-resistance mutations (see table below).

The morph was generated by Proteopedia's PyMOL Morpher. 1tw7 was pre-aligned with 1hxw, aligning only residues 1-35. Alignment was done in the Jmol Java Application with the following script:

load =1hxw # "=" means load from RCSB PDB.
load append =1tw7 # add this model rather than replacing the previously loaded model.
frame all # display both models.
background white
trace only
color polymer
delay 2.0
compare {2.1} {1.1} subset {*.ca} atoms {1-35} {1-35} rotate translate 2.0 # moves model 2 to align with model 1
select 2.1 # "2.1" is the second model loaded
write 1tw7-aligned-to-1hxw.pdb

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

L10I, D25N, M36V, M46L, I54V, I62V, L63P, A71V, V82A, I84V, L90M

3phv

2pc0

2007

1.4 Å; BTA*

1 chain

12.2 Å

Q7K

2r8n

2008

1.2 Å; A*

1 chain

12.19 Å

Q7K, L33I, K41R, L63I

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, D25N, D35E, I36V, M46L, T82A; 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.
† Distance between the Ile50 alpha carbons in each chain. These are near the tips of the flaps, and this distance is commonly used in the literature to measure the openness of the flaps.


References

  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.

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