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PDBsum entry 1fko
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protein ligands Protein-protein interface(s) links
Transferase PDB id
1fko

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
543 a.a. *
403 a.a. *
Ligands
EFZ
* Residue conservation analysis
PDB id:
1fko
Name: Transferase
Title: Crystal structure of nnrti resistant k103n mutant HIV-1 reverse transcriptase in complex with dmp-266(efavirenz)
Structure: HIV-1 rt, a-chain. Chain: a. Fragment: p66. Engineered: yes. Mutation: yes. Other_details: complexed with dmp-266(efavirenz). HIV-1 rt, b-chain. Chain: b. Fragment: p51.
Source: Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: hxb2 isolate. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
2.90Å     R-factor:   0.205     R-free:   0.287
Authors: J.Ren,J.Milton,K.L.Weaver,S.A.Short,D.I.Stuart,D.K.Stammers
Key ref:
J.Ren et al. (2000). Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. Structure, 8, 1089-1094. PubMed id: 11080630 DOI: 10.1016/S0969-2126(00)00513-X
Date:
10-Aug-00     Release date:   03-Nov-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04585  (POL_HV1H2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1435 a.a.
543 a.a.*
Protein chain
Pfam   ArchSchema ?
P04585  (POL_HV1H2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1435 a.a.
403 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: Chains A, B: E.C.2.7.7.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 2: Chains A, B: 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: Chains A, B: 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: Chains A, B: E.C.3.1.-.-
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 5: Chains A, B: 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: Chains A, B: E.C.3.1.26.13  - retroviral ribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 7: Chains A, B: 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: 10.1016/S0969-2126(00)00513-X Structure 8:1089-1094 (2000)
PubMed id: 11080630  
 
 
Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase.
J.Ren, J.Milton, K.L.Weaver, S.A.Short, D.I.Stuart, D.K.Stammers.
 
  ABSTRACT  
 
BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Omit MapsSimulated-annealing omit electron density maps for the inhibitors and certain sidechains: (a) efavirenz-RT(wild-type); (b) efavirenz-RT(K103N), Asn103, and Tyr181; (c) nevirapine-RT(K103N) and Asn103. The maps are contoured at 4s

 
  The above figure is reprinted by permission from Cell Press: Structure (2000, 8, 1089-1094) copyright 2000.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23314251 M.Lapkouski, L.Tian, J.T.Miller, S.F.Le Grice, and W.Yang (2013).
Complexes of HIV-1 RT, NNRTI and RNA/DNA hybrid reveal a structure compatible with RNA degradation.
  Nat Struct Mol Biol, 20, 230-236.
PDB codes: 4b3o 4b3p 4b3q
20583854 P.Decha, P.Intharathep, T.Udommaneethanakit, P.Sompornpisut, S.Hannongbua, P.Wolschann, and V.Parasuk (2011).
Theoretical studies on the molecular basis of HIV-1RT/NNRTIs interactions.
  J Enzyme Inhib Med Chem, 26, 29-36.  
21449841 S.Ibe, and W.Sugiura (2011).
Clinical significance of HIV reverse-transcriptase inhibitor-resistance mutations.
  Future Microbiol, 6, 295-315.  
19901096 A.G.Marcelin, P.Flandre, D.Descamps, L.Morand-Joubert, C.Charpentier, J.Izopet, M.A.Trabaud, H.Saoudin, C.Delaugerre, C.Tamalet, J.Cottalorda, M.Bouvier-Alias, D.Bettinger, G.Dos Santos, A.Ruffault, C.Alloui, C.Henquell, S.Rogez, F.Barin, A.Signori-Schmuck, S.Vallet, B.Masquelier, V.Calvez, C.Alloui, D.Bettinger, G.Anies, B.Masquelier, S.Vallet, C.Henquell, M.Bouvier-Alias, G.Dos Santos, A.Signori-Schmuck, S.Rogez, P.Andre, J.C.Tardy, M.A.Trabaud, C.Tamalet, B.Montes, J.Cottalorda, D.Descamps, F.Brun-Vézinet, C.Charpentier, M.L.Chaix, S.Fourati, A.G.Marcelin, V.Calvez, P.Flandre, L.Morand-Joubert, C.Delaugerre, A.Ruffault, A.Maillard, T.Bourlet, H.Saoudin, J.Izopet, F.Barin, O.Bouchaud, B.Hoen, M.Dupon, P.Morlat, D.Neau, M.Garré, V.Bellein, C.Jacomet, Y.Lévy, S.Dominguez, A.Cabié, P.Leclercq, P.Weinbreck, L.Cotte, I.Poizot-Martin, I.Ravaud, J.Reynes, P.Dellamonica, P.Yeni, R.Landman, L.Weiss, C.Piketty, J.P.Viard, C.Katlama, A.Simon, P.M.Girard, J.L.Meynard, J.M.Molina, M.T.Goeger-Sow, I.Lamaury, C.Michelet, F.Lucht, B.Marchou, P.Massip, and J.M.Besnier (2010).
Factors associated with virological response to etravirine in nonnucleoside reverse transcriptase inhibitor-experienced HIV-1-infected patients.
  Antimicrob Agents Chemother, 54, 72-77.  
20376302 K.Singh, B.Marchand, K.A.Kirby, E.Michailidis, and S.G.Sarafianos (2010).
Structural Aspects of Drug Resistance and Inhibition of HIV-1 Reverse Transcriptase.
  Viruses, 2, 606-638.  
  20122159 M.E.Abram, S.G.Sarafianos, and M.A.Parniak (2010).
The mutation T477A in HIV-1 reverse transcriptase (RT) restores normal proteolytic processing of RT in virus with Gag-Pol mutated in the p51-RNH cleavage site.
  Retrovirology, 7, 6.  
19959199 R.Sakuma, T.Sakuma, S.Ohmine, R.H.Silverman, and Y.Ikeda (2010).
Xenotropic murine leukemia virus-related virus is susceptible to AZT.
  Virology, 397, 1-6.  
20039714 V.A.Braz, L.A.Holladay, and M.D.Barkley (2010).
Efavirenz binding to HIV-1 reverse transcriptase monomers and dimers.
  Biochemistry, 49, 601-610.  
19775780 A.Carta, S.Pricl, S.Piras, M.Fermeglia, P.La Colla, and R.Loddo (2009).
Activity and molecular modeling of a new small molecule active against NNRTI-resistant HIV-1 mutants.
  Eur J Med Chem, 44, 5117-5122.  
19374380 S.E.Nichols, R.A.Domaoal, V.V.Thakur, J.Tirado-Rives, K.S.Anderson, and W.L.Jorgensen (2009).
Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures.
  J Chem Inf Model, 49, 1272-1279.  
19637180 Y.M.Loksha, E.B.Pedersen, R.Loddo, and P.La Colla (2009).
Synthesis and anti-HIV-1 activity of 1-substiuted 6-(3-cyanobenzoyl) and [(3-cyanophenyl)fluoromethyl]-5-ethyl-uracils.
  Arch Pharm (Weinheim), 342, 501-506.  
18832874 K.Deforche, R.J.Camacho, Z.Grossman, M.A.Soares, K.Van Laethem, D.A.Katzenstein, P.R.Harrigan, R.Kantor, R.Shafer, A.M.Vandamme, R.Kantor, D.A.Katzenstein, R.W.Shafer, R.J.Camacho, A.P.Carvalho, B.Wynhoven, P.R.Harrigan, P.Cane, J.Clarke, J.Weber, S.Sirivichayakul, P.Phanuphak, M.A.Soares, A.Tanuri, J.Snoeck, A.M.Vandamme, L.Morris, H.Rudich, Z.Grossman, J.M.Schapiro, R.Rodrigues, L.F.Brigido, A.Holguin, V.Soriano, K.Ariyoshi, W.Sugiura, M.B.Bouzas, P.Cahn, D.Pillay, T.L.Katzenstein, and L.B.Jørgensen (2008).
Bayesian network analyses of resistance pathways against efavirenz and nevirapine.
  AIDS, 22, 2107-2115.  
18338369 P.Srivab, and S.Hannongbua (2008).
A study of the binding energies of efavirenz to wild-type and K103N/Y181C HIV-1 reverse transcriptase based on the ONIOM method.
  ChemMedChem, 3, 803-811.  
17949071 G.Barreiro, C.R.Guimarães, I.Tubert-Brohman, T.M.Lyons, J.Tirado-Rives, and W.L.Jorgensen (2007).
Search for non-nucleoside inhibitors of HIV-1 reverse transcriptase using chemical similarity, molecular docking, and MM-GB/SA scoring.
  J Chem Inf Model, 47, 2416-2428.  
16969668 R.K.Rawal, A.Kumar, M.I.Siddiqi, and S.B.Katti (2007).
Molecular docking studies on 4-thiazolidinones as HIV-1 RT inhibitors.
  J Mol Model, 13, 155-161.  
17370068 Y.El Safadi, V.Vivet-Boudou, and R.Marquet (2007).
HIV-1 reverse transcriptase inhibitors.
  Appl Microbiol Biotechnol, 75, 723-737.  
17116677 Z.Zhang, W.Xu, Y.H.Koh, J.H.Shim, J.L.Girardet, L.T.Yeh, R.K.Hamatake, and Z.Hong (2007).
A novel nonnucleoside analogue that inhibits human immunodeficiency virus type 1 isolates resistant to current nonnucleoside reverse transcriptase inhibitors.
  Antimicrob Agents Chemother, 51, 429-437.  
16911530 J.Ren, C.E.Nichols, A.Stamp, P.P.Chamberlain, R.Ferris, K.L.Weaver, S.A.Short, and D.K.Stammers (2006).
Structural insights into mechanisms of non-nucleoside drug resistance for HIV-1 reverse transcriptases mutated at codons 101 or 138.
  FEBS J, 273, 3850-3860.
PDB codes: 2hnd 2hny 2hnz
16075442 T.Billard (2006).
Synthetic applications of beta-fluoroalkylated alpha,beta-unsaturated carbonyl compounds.
  Chemistry, 12, 974-979.  
16508186 T.Maruyama, S.Kozai, Y.Demizu, M.Witvrouw, C.Pannecouque, J.Balzarini, R.Snoecks, G.Andrei, and E.De Clercq (2006).
Synthesis and anti-HIV-1 and anti-HCMV activity of 1-substituted 3-(3,5-dimethylbenzyl)uracil derivatives.
  Chem Pharm Bull (Tokyo), 54, 325-333.  
16897578 Z.Zhang, M.Zheng, L.Du, J.Shen, X.Luo, W.Zhu, and H.Jiang (2006).
Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues.
  J Comput Aided Mol Des, 20, 281-293.  
15790559 I.Oz Gleenberg, O.Avidan, Y.Goldgur, A.Herschhorn, and A.Hizi (2005).
Peptides derived from the reverse transcriptase of human immunodeficiency virus type 1 as novel inhibitors of the viral integrase.
  J Biol Chem, 280, 21987-21996.  
16163450 J.L.Medina-Franco, A.Golbraikh, S.Oloff, R.Castillo, and A.Tropsha (2005).
Quantitative structure-activity relationship analysis of pyridinone HIV-1 reverse transcriptase inhibitors using the k nearest neighbor method and QSAR-based database mining.
  J Comput Aided Mol Des, 19, 229-242.  
15602767 S.Roussel, T.Billard, B.R.Langlois, and L.Saint-James (2005).
Towards enantioselective nucleophilic trifluoromethylation.
  Chemistry, 11, 939-944.  
16200637 W.L.Jorgensen, and J.Tirado-Rives (2005).
Molecular modeling of organic and biomolecular systems using BOSS and MCPRO.
  J Comput Chem, 26, 1689-1700.  
16114038 X.He, Y.Mei, Y.Xiang, D.W.Zhang, and J.Z.Zhang (2005).
Quantum computational analysis for drug resistance of HIV-1 reverse transcriptase to nevirapine through point mutations.
  Proteins, 61, 423-432.  
15789428 Y.Mei, X.He, Y.Xiang, D.W.Zhang, and J.Z.Zhang (2005).
Quantum study of mutational effect in binding of efavirenz to HIV-1 RT.
  Proteins, 59, 489-495.  
14748000 F.Daeyaert, M.de Jonge, J.Heeres, L.Koymans, P.Lewi, M.H.Vinkers, and P.A.Janssen (2004).
A pharmacophore docking algorithm and its application to the cross-docking of 18 HIV-NNRTI's in their binding pockets.
  Proteins, 54, 526-533.  
15122639 J.A.Olsen, D.W.Banner, P.Seiler, B.Wagner, T.Tschopp, U.Obst-Sander, M.Kansy, K.Müller, and F.Diederich (2004).
Fluorine interactions at the thrombin active site: protein backbone fragments H-C(alpha)-C=O comprise a favorable C-F environment and interactions of C-F with electrophiles.
  Chembiochem, 5, 666-675.  
15544453 N.Sluis-Cremer, N.A.Temiz, and I.Bahar (2004).
Conformational changes in HIV-1 reverse transcriptase induced by nonnucleoside reverse transcriptase inhibitor binding.
  Curr HIV Res, 2, 323-332.  
15482105 J.A.Turpin (2003).
The next generation of HIV/AIDS drugs: novel and developmental antiHIV drugs and targets.
  Expert Rev Anti Infect Ther, 1, 97.  
11895437 J.Lindberg, S.Sigurdsson, S.Löwgren, H.O.Andersson, C.Sahlberg, R.Noréen, K.Fridborg, H.Zhang, and T.Unge (2002).
Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant.
  Eur J Biochem, 269, 1670-1677.
PDB codes: 1ikv 1ikw 1ikx 1iky
12386343 J.Ren, L.E.Bird, P.P.Chamberlain, G.B.Stewart-Jones, D.I.Stuart, and D.K.Stammers (2002).
Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors.
  Proc Natl Acad Sci U S A, 99, 14410-14415.
PDB code: 1mu2
11416202 G.Tachedjian, M.Orlova, S.G.Sarafianos, E.Arnold, and S.P.Goff (2001).
Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV type 1 reverse transcriptase.
  Proc Natl Acad Sci U S A, 98, 7188-7193.  
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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