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PDBsum entry 2aoc
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Hydrolase/hydrolase inhibitor PDB id
2aoc

 

 

 

 

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Contents
Protein chains
99 a.a. *
Ligands
UNX
DMS ×3
GOL ×2
2NC
Metals
_NA
_CL ×3
Waters ×239
* Residue conservation analysis
PDB id:
2aoc
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure analysis of HIV-1 protease mutant i84v with a substrate analog p2-nc
Structure: HIV-1 protease. Chain: a, b. Synonym: retropepsin. Engineered: yes. Mutation: yes
Source: Human immunodeficiency virus type 1 (bh5 isolate). Organism_taxid: 11682. Strain: bh5 isolate. Gene: pol. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Trimer (from PQS)
Resolution:
1.30Å     R-factor:   0.126     R-free:   0.166
Authors: Y.Tie,P.I.Boross,Y.F.Wang,L.Gaddis,F.Liu,X.Chen,J.Tozser, R.W.Harrison,I.T.Weber
Key ref:
Y.Tie et al. (2005). Molecular basis for substrate recognition and drug resistance from 1.1 to 1.6 angstroms resolution crystal structures of HIV-1 protease mutants with substrate analogs. FEBS J, 272, 5265-5277. PubMed id: 16218957 DOI: 10.1111/j.1742-4658.2005.04923.x
Date:
12-Aug-05     Release date:   17-Jan-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
P04587  (POL_HV1B5) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BH5)
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1447 a.a.
99 a.a.*
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: E.C.2.7.7.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 2: E.C.2.7.7.49  - RNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
DNA(n)
 + 2'-deoxyribonucleoside 5'-triphosphate
 = DNA(n+1)
 + diphosphate
   Enzyme class 3: E.C.2.7.7.7  - DNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
DNA(n)
 + 2'-deoxyribonucleoside 5'-triphosphate
 = DNA(n+1)
 + diphosphate
   Enzyme class 4: E.C.3.1.-.-
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 5: E.C.3.1.13.2  - exoribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Exonucleolytic cleavage to 5'-phosphomonoester oligonucleotides in both 5'- to 3'- and 3'- to 5'-directions.
   Enzyme class 6: E.C.3.1.26.13  - retroviral ribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 7: E.C.3.4.23.16  - HIV-1 retropepsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1111/j.1742-4658.2005.04923.x FEBS J 272:5265-5277 (2005)
PubMed id: 16218957  
 
 
Molecular basis for substrate recognition and drug resistance from 1.1 to 1.6 angstroms resolution crystal structures of HIV-1 protease mutants with substrate analogs.
Y.Tie, P.I.Boross, Y.F.Wang, L.Gaddis, F.Liu, X.Chen, J.Tozser, R.W.Harrison, I.T.Weber.
 
  ABSTRACT  
 
HIV-1 protease (PR) and two drug-resistant variants--PR with the V82A mutation (PR(V82A)) and PR with the I84V mutation (PR(I84V))--were studied using reduced peptide analogs of five natural cleavage sites (CA-p2, p2-NC, p6pol-PR, p1-p6 and NC-p1) to understand the structural and kinetic changes. The common drug-resistant mutations V82A and I84V alter residues forming the substrate-binding site. Eight crystal structures were refined at resolutions of 1.10-1.60 A. Differences in the PR-analog interactions depended on the peptide sequence and were consistent with the relative inhibition. Analog p6(pol)-PR formed more hydrogen bonds of P2 Asn with PR and fewer van der Waals contacts at P1' Pro compared with those formed by CA-p2 or p2-NC in PR complexes. The P3 Gly in p1-p6 provided fewer van der Waals contacts and hydrogen bonds at P2-P3 and more water-mediated interactions. PR(I84V) showed reduced van der Waals interactions with inhibitor compared with PR, which was consistent with kinetic data. The structures suggest that the binding affinity for mutants is modulated by the conformational flexibility of the substrate analogs. The complexes of PR(V82A) showed smaller shifts of the main chain atoms of Ala82 relative to PR, but more movement of the peptide analog, compared to complexes with clinical inhibitors. PR(V82A) was able to compensate for the loss of interaction with inhibitor caused by mutation, in agreement with kinetic data, but substrate analogs have more flexibility than the drugs to accommodate the structural changes caused by mutation. Hence, these structures help to explain how HIV can develop drug resistance while retaining the ability of PR to hydrolyze natural substrates.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Electron density map of HIV-1 protease with the V82A mutation (PR[V82A])–p2-NC crystal structure. The 2Fo–Fc map was contoured at a level of 2.2 . Hydrogen bond interactions are shown with distances in Å. (A) Residues 78–82. (B) Asp30 interacting with P2' Gln. 		Figure 7.
Fig. 7. Structural variation around the active site. (A) PR–p1-p6 is shown (colored by atom type) superimposed on D25N–p1-p6 (1KJF) in green bonds. Distances within 4.0 Šare shown. (B) PR–UIC-94017 is shown as yellow bonds superimposed on PR–p1-p6 complex (colored by atom type).
 
  The above figures are reprinted from an Open Access publication published by the Federation of European Biochemical Societies: FEBS J (2005, 272, 5265-5277) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20480379 H.Ode, M.Yokoyama, T.Kanda, and H.Sato (2011).
Identification of folding preferences of cleavage junctions of HIV-1 precursor proteins for regulation of cleavability.
  J Mol Model, 17, 391-399.  
21394574 Z.Liu, Y.Wang, J.Brunzelle, I.A.Kovari, and L.C.Kovari (2011).
Nine crystal structures determine the substrate envelope of the MDR HIV-1 protease.
  Protein J, 30, 173-183.
PDB codes: 3ots 3oty 3ou1 3ou3 3ou4 3oua 3oub 3ouc 3oud
20695887 C.H.Shen, Y.F.Wang, A.Y.Kovalevsky, R.W.Harrison, and I.T.Weber (2010).
Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters.
  FEBS J, 277, 3699-3714.
PDB codes: 3nu3 3nu4 3nu5 3nu6 3nu9 3nuj 3nuo
20195662 P.Dirauf, H.Meiselbach, and H.Sticht (2010).
Effects of the V82A and I54V mutations on the dynamics and ligand binding properties of HIV-1 protease.
  J Mol Model, 16, 1577-1583.  
19899162 R.Ishima, Q.Gong, Y.Tie, I.T.Weber, and J.M.Louis (2010).
Highly conserved glycine 86 and arginine 87 residues contribute differently to the structure and activity of the mature HIV-1 protease.
  Proteins, 78, 1015-1025.
PDB codes: 3jvw 3jvy 3jw2
19746963 A.K.Ghosh, S.Kulkarni, D.D.Anderson, L.Hong, A.Baldridge, Y.F.Wang, A.A.Chumanevich, A.Y.Kovalevsky, Y.Tojo, M.Amano, Y.Koh, J.Tang, I.T.Weber, and H.Mitsuya (2009).
Design, synthesis, protein-ligand X-ray structure, and biological evaluation of a series of novel macrocyclic human immunodeficiency virus-1 protease inhibitors to combat drug resistance.
  J Med Chem, 52, 7689-7705.
PDB codes: 3i6o 3i7e
19473017 A.K.Ghosh, S.Leshchenko-Yashchuk, D.D.Anderson, A.Baldridge, M.Noetzel, H.B.Miller, Y.Tie, Y.F.Wang, Y.Koh, I.T.Weber, and H.Mitsuya (2009).
Design of HIV-1 protease inhibitors with pyrrolidinones and oxazolidinones as novel P1'-ligands to enhance backbone-binding interactions with protease: synthesis, biological evaluation, and protein-ligand X-ray studies.
  J Med Chem, 52, 3902-3914.
PDB code: 3h5b
18781587 E.S.Bolstad, and A.C.Anderson (2009).
In pursuit of virtual lead optimization: pruning ensembles of receptor structures for increased efficiency and accuracy during docking.
  Proteins, 75, 62-74.  
20004167 S.Chaudhury, and J.J.Gray (2009).
Identification of structural mechanisms of HIV-1 protease specificity using computational peptide docking: implications for drug resistance.
  Structure, 17, 1636-1648.  
18783203 A.K.Ghosh, S.Gemma, A.Baldridge, Y.F.Wang, A.Y.Kovalevsky, Y.Koh, I.T.Weber, and H.Mitsuya (2008).
Flexible cyclic ethers/polyethers as novel P2-ligands for HIV-1 protease inhibitors: design, synthesis, biological evaluation, and protein-ligand X-ray studies.
  J Med Chem, 51, 6021-6033.
PDB code: 3djk
18843400 A.K.Ghosh, S.Gemma, J.Takayama, A.Baldridge, S.Leshchenko-Yashchuk, H.B.Miller, Y.F.Wang, A.Y.Kovalevsky, Y.Koh, I.T.Weber, and H.Mitsuya (2008).
Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies.
  Org Biomol Chem, 6, 3703-3713.
PDB code: 3dk1
  18820715 E.Lefebvre, and C.A.Schiffer (2008).
Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir.
  AIDS Rev, 10, 131-142.  
18597780 F.Liu, A.Y.Kovalevsky, Y.Tie, A.K.Ghosh, R.W.Harrison, and I.T.Weber (2008).
Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir.
  J Mol Biol, 381, 102-115.
PDB codes: 3cyw 3cyx 3d1x 3d1y 3d1z 3d20
18701588 H.Eizert, P.Bander, P.Bagossi, T.Sperka, G.Miklóssy, P.Boross, I.T.Weber, and J.Tözsér (2008).
Amino acid preferences of retroviral proteases for amino-terminal positions in a type 1 cleavage site.
  J Virol, 82, 10111-10117.  
18281688 J.M.Sayer, F.Liu, R.Ishima, I.T.Weber, and J.M.Louis (2008).
Effect of the active site D25N mutation on the structure, stability, and ligand binding of the mature HIV-1 protease.
  J Biol Chem, 283, 13459-13470.
PDB codes: 3bva 3bvb
17729291 M.D.Altman, E.A.Nalivaika, M.Prabu-Jeyabalan, C.A.Schiffer, and B.Tidor (2008).
Computational design and experimental study of tighter binding peptides to an inactivated mutant of HIV-1 protease.
  Proteins, 70, 678-694.
PDB codes: 2nxd 2nxl 2nxm
18823110 M.J.Giffin, H.Heaslet, A.Brik, Y.C.Lin, G.Cauvi, C.H.Wong, D.E.McRee, J.H.Elder, C.D.Stout, and B.E.Torbett (2008).
A copper(I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant.
  J Med Chem, 51, 6263-6270.  
18768960 S.Mosebi, L.Morris, H.W.Dirr, and Y.Sayed (2008).
Active-site mutations in the South african human immunodeficiency virus type 1 subtype C protease have a significant impact on clinical inhibitor binding: kinetic and thermodynamic study.
  J Virol, 82, 11476-11479.  
18052235 A.Y.Kovalevsky, A.A.Chumanevich, F.Liu, J.M.Louis, and I.T.Weber (2007).
Caught in the Act: the 1.5 A resolution crystal structures of the HIV-1 protease and the I54V mutant reveal a tetrahedral reaction intermediate.
  Biochemistry, 46, 14854-14864.
PDB codes: 3b7v 3b80
17696515 Y.F.Wang, Y.Tie, P.I.Boross, J.Tozser, A.K.Ghosh, R.W.Harrison, and I.T.Weber (2007).
Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease.
  J Med Chem, 50, 4509-4515.
PDB codes: 2qci 2qd6 2qd7 2qd8 2z4o
17243183 Y.Tie, A.Y.Kovalevsky, P.Boross, Y.F.Wang, A.K.Ghosh, J.Tozser, R.W.Harrison, and I.T.Weber (2007).
Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir.
  Proteins, 67, 232-242.
PDB codes: 2nmw 2nmy 2nmz 2nnk 2nnp 3oxc
16962136 A.Y.Kovalevsky, F.Liu, S.Leshchenko, A.K.Ghosh, J.M.Louis, R.W.Harrison, and I.T.Weber (2006).
Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114.
  J Mol Biol, 363, 161-173.
PDB codes: 2hs1 2hs2
16277992 F.Liu, P.I.Boross, Y.F.Wang, J.Tozser, J.M.Louis, R.W.Harrison, and I.T.Weber (2005).
Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S.
  J Mol Biol, 354, 789-800.
PDB codes: 2avm 2avo 2avq 2avs 2avv
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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