Structures of Protease
To retrieve HIV Protease (PR) structures from the PDB, we performed an advanced query for structures having similar sequences (search parameters: BLAST search, e-value cutoff = 10-20, query sequence), and exported the data into a spreadsheet using the menu options on the left side of the page.
386 structures were identified (363 HIV-1, 16 HIV-2, 7 SIV). The structures could be categorized as follows: (i) unliganded PR, (ii) PR bound to substrates, (iii) PR bound to inhibitors, (iv) PR with PI-resistance mutations, and (v) PR of different subtypes.
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| Unliganded PR |
1ODW,
1RPI,
2HVP,
2PC0,
2HB2,
2HB4,
3PHV |
| PR bound to substrates |
1YTH,
1KJ4,
1KJ7,
1KJF,
1KJG,
1YTG,
1KJH,
1A8K,
2NPH,
3BXR,
3BXS,
3DOX |
| PR bound to inhibitors |
APV: 1HPV;
ATV: 2FXE;
DRV: 1T3R,
1T7I,
2IEN,
2HS1;
IDV: 1HSG;
LPV: 1MUI;
NFV: 1OHR;
RTV: 1HXW;
SQV: 2NMW;
TPV: 1D4Y |
| Resistance mutations |
1DAZ,
1D4S,
1FB7,
1FGC,
1FG6,
1FEJ,
1FF0,
1FFI,
1F7A,
1FFF,
1FG8,
1T7J,
1TSQ,
1TSU,
1TW7,
1MT7,
1MT8,
1MT9,
1MTB,
1K1U,
1K2B,
1K2C,
1K1T,
1RPI,
1RV7,
1RL8,
1N49,
1SDT,
1SDU,
1SDV,
1SGU,
1SH9,
1ZGA,
2G69,
2FXD,
2F80,
2F81,
2F8G,
2HS2,
2IDW,
2IEO,
2AVO,
2AVS,
2AVV,
2B7Z,
2B60,
2PYM,
2PYN,
2Q63,
2Q64,
2QAK,
2O4P,
2O4L,
2NMW,
2NMY,
2NMZ,
2NNK,
2NNP,
2QHC,
2RKF,
2RKG,
2Z54,
3B7V,
3B80,
3BVA,
3BVB,
3CYW,
3CYX,
3D1X,
3D1Y,
3D1Z,
3D20 |
| Different subtypes |
2P3A,
2P3B,
2P3C,
2P3D,
2R8N,
2AQU
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The HIV-1 protease enzyme is responsible for the post-translational processing of the viral gag- and gag-pol polyproteins to yield the structural proteins and enzymes of the virus. The enzyme is an aspartic protease composed of two noncovalently associated, structurally identical monomers 99 amino acids in length. The hydrophobic substrate cleft recognizes and cleaves 9 different peptide sequences to produce the matrix, capsid, nucleocapsid, and p6 proteins from the gag polyprotein and the protease, RT, and integrase proteins from the gag-pol polyprotein.
This figure shows the crystallographic structure of wildtype HIV-1 protease bound to lopinavir (Stoll V, 2002, 1MUI). The protease active site resembles that of other aspartic proteases and contains the conserved triad, Asp-Thr-Gly, at positions 25 to 27 (shown as white sticks). The enzyme contains a flexible flap region that closes down on the active site upon substrate binding consisting of residues 46 to 56 (Wlodawer A, 1993). The substrate cleft residues are shown in pale yellow: R8, L23, D25-37, D29, D30, V32, I47, G48, I50, V82, I84.
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This figure shows the major PI-resistance positions including those in the substrate cleft: L23, D30, V332, I47, G48, I50, V82, I84; Major non-cleft flap positions include M46, F53, and I54; and Major non-cleft, non-flap positions include L24, L33, L76, N88, L90.
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This figure shows the major PI-resistance mutations in red, as well as another 9 postions that have been selected by PIs and are associated with decreased PI susceptibility: L10, V11, K43, Q58, T74, V71, G73, N83, L89.
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