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PDBsum entry 2f81
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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
2f81

 

 

 

 

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Contents
Protein chains
99 a.a. *
Ligands
017
GOL ×2
Metals
_NA
_CL ×2
Waters ×213
* Residue conservation analysis
PDB id:
2f81
Name: Hydrolase
Title: HIV-1 protease mutant l90m complexed with inhibitor tmc114
Structure: Pol polyprotein. Chain: a, b. Fragment: protease (retropepsin). Engineered: yes. Mutation: yes
Source: Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: bh5 isolate. Gene: pol. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
1.25Å     R-factor:   0.144     R-free:   0.189
Authors: A.Y.Kovalevsky,I.T.Weber
Key ref: A.Y.Kovalevsky et al. (2006). Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. J Med Chem, 49, 1379-1387. PubMed id: 16480273 DOI: 10.1021/jm050943c
Date:
01-Dec-05     Release date:   07-Mar-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: 10.1021/jm050943c J Med Chem 49:1379-1387 (2006)
PubMed id: 16480273  
 
 
Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M.
A.Y.Kovalevsky, Y.Tie, F.Liu, P.I.Boross, Y.F.Wang, S.Leshchenko, A.K.Ghosh, R.W.Harrison, I.T.Weber.
 
  ABSTRACT  
 
The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20827746 A.K.Ghosh, C.X.Xu, K.V.Rao, A.Baldridge, J.Agniswamy, Y.F.Wang, I.T.Weber, M.Aoki, S.G.Miguel, M.Amano, and H.Mitsuya (2010).
Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors.
  ChemMedChem, 5, 1850-1854.
PDB code: 3ok9
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
19629548 J.Chen, S.Zhang, X.Liu, and Q.Zhang (2010).
Insights into drug resistance of mutations D30N and I50V to HIV-1 protease inhibitor TMC-114: free energy calculation and molecular dynamic simulation.
  J Mol Model, 16, 459-468.  
20737578 J.M.Sayer, J.Agniswamy, I.T.Weber, and J.M.Louis (2010).
Autocatalytic maturation, physical/chemical properties, and crystal structure of group N HIV-1 protease: relevance to drug resistance.
  Protein Sci, 19, 2055-2072.
PDB code: 3mws
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
19400736 A.J.Kandathil, A.P.Joseph, R.Kannangai, N.Srinivasan, O.C.Abraham, S.A.Pulimood, and G.Sridharan (2009).
Structural basis of drug resistance by genetic variants of HIV type 1 clade c protease from India.
  AIDS Res Hum Retroviruses, 25, 511-519.  
19323561 A.K.Ghosh (2009).
Harnessing nature's insight: design of aspartyl protease inhibitors from treatment of drug-resistant HIV to Alzheimer's disease.
  J Med Chem, 52, 2163-2176.  
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
19928916 D.Das, Y.Koh, Y.Tojo, A.K.Ghosh, and H.Mitsuya (2009).
Prediction of potency of protease inhibitors using free energy simulations with polarizable quantum mechanics-based ligand charges and a hybrid water model.
  J Chem Inf Model, 49, 2851-2862.  
19535439 K.G.Sasková, M.Kozísek, P.Rezácová, J.Brynda, T.Yashina, R.M.Kagan, and J.Konvalinka (2009).
Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir.
  J Virol, 83, 8810-8818.
PDB codes: 3ggt 3ggu 3u7s
18808097 A.Y.Kovalevsky, A.K.Ghosh, and I.T.Weber (2008).
Solution kinetics measurements suggest HIV-1 protease has two binding sites for darunavir and amprenavir.
  J Med Chem, 51, 6599-6603.  
18834890 A.Y.Kovalevsky, J.M.Louis, A.Aniana, A.K.Ghosh, and I.T.Weber (2008).
Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease.
  J Mol Biol, 384, 178-192.
PDB codes: 3ebz 3ec0 3ecg
  19209258 C.L.Tremblay (2008).
Combating HIV resistance - focus on darunavir.
  Ther Clin Risk Manag, 4, 759-766.  
  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
18754631 X.Chen, I.Weber, and R.W.Harrison (2008).
Hydration water and bulk water in proteins have distinct properties in radial distributions calculated from 105 atomic resolution crystal structures.
  J Phys Chem B, 112, 12073-12080.  
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
17371811 M.Amano, Y.Koh, D.Das, J.Li, S.Leschenko, Y.F.Wang, P.I.Boross, I.T.Weber, A.K.Ghosh, and H.Mitsuya (2007).
A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
  Antimicrob Agents Chemother, 51, 2143-2155.  
17917268 M.Takahashi, Y.Kudaka, N.Okumura, A.Hirano, K.Banno, and T.Kaneda (2007).
The validation of plasma darunavir concentrations determined by the HPLC method for protease inhibitors.
  Biol Pharm Bull, 30, 1947-1949.  
17623840 S.A.Seibold, and R.I.Cukier (2007).
A molecular dynamics study comparing a wild-type with a multiple drug resistant HIV protease: differences in flap and aspartate 25 cavity dimensions.
  Proteins, 69, 551-565.  
17360759 S.Muzammil, A.A.Armstrong, L.W.Kang, A.Jakalian, P.R.Bonneau, V.Schmelmer, L.M.Amzel, and E.Freire (2007).
Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 protease drug resistance mutations.
  J Virol, 81, 5144-5154.
PDB codes: 2o4k 2o4l 2o4n 2o4p 2o4s
17581235 V.Lafont, A.A.Armstrong, H.Ohtaka, Y.Kiso, L.Mario Amzel, and E.Freire (2007).
Compensating enthalpic and entropic changes hinder binding affinity optimization.
  Chem Biol Drug Des, 69, 413-422.
PDB codes: 2pk5 2pk6
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
17635930 Y.Koh, S.Matsumi, D.Das, M.Amano, D.A.Davis, J.Li, S.Leschenko, A.Baldridge, T.Shioda, R.Yarchoan, A.K.Ghosh, and H.Mitsuya (2007).
Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization.
  J Biol Chem, 282, 28709-28720.  
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
16927344 A.K.Ghosh, P.Ramu Sridhar, N.Kumaragurubaran, Y.Koh, I.T.Weber, and H.Mitsuya (2006).
Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of hiv protease inhibitors that combat drug resistance.
  ChemMedChem, 1, 939-950.  
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
17108976 N.S.Gray (2006).
Drug discovery through industry-academic partnerships.
  Nat Chem Biol, 2, 649-653.  
17209774 Y.Mitsuya, M.A.Winters, W.J.Fessel, S.Y.Rhee, L.Hurley, M.Horberg, C.A.Schiffer, A.R.Zolopa, and R.W.Shafer (2006).
N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure.
  AIDS Res Hum Retroviruses, 22, 1300-1305.  
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 code is shown on the right.

 

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