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PDBsum entry 1hiv

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protein ligands Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1hiv
Jmol
Contents
Protein chains
99 a.a. *
Ligands
1ZK
Waters ×90
* Residue conservation analysis
PDB id:
1hiv
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of a complex of HIV-1 protease with a dihydroethylene-containing inhibitor: comparisons with mole modeling
Structure: HIV-1 protease. Chain: a, b. Engineered: yes
Source: Human immunodeficiency virus 1. Organism_taxid: 11676. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.00Å     R-factor:   0.169    
Authors: N.Thanki,A.Wlodawer
Key ref: N.Thanki et al. (1992). Crystal structure of a complex of HIV-1 protease with a dihydroxyethylene-containing inhibitor: comparisons with molecular modeling. Protein Sci, 1, 1061-1072. PubMed id: 1304383 DOI: 10.1002/pro.5560010811
Date:
12-Feb-92     Release date:   31-Oct-93    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P04585  (POL_HV1H2) -  Gag-Pol polyprotein
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1435 a.a.
99 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 1: E.C.2.7.7.49  - RNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)
Deoxynucleoside triphosphate
+ DNA(n)
= diphosphate
+ DNA(n+1)
   Enzyme class 2: E.C.2.7.7.7  - DNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)
Deoxynucleoside triphosphate
+ DNA(n)
= diphosphate
+ DNA(n+1)
   Enzyme class 3: 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 4: E.C.3.1.26.13  - Retroviral ribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 5: 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
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     aspartic-type endopeptidase activity     1 term  

 

 
    reference    
 
 
DOI no: 10.1002/pro.5560010811 Protein Sci 1:1061-1072 (1992)
PubMed id: 1304383  
 
 
Crystal structure of a complex of HIV-1 protease with a dihydroxyethylene-containing inhibitor: comparisons with molecular modeling.
N.Thanki, J.K.Rao, S.I.Foundling, W.J.Howe, J.B.Moon, J.O.Hui, A.G.Tomasselli, R.L.Heinrikson, S.Thaisrivongs, A.Wlodawer.
 
  ABSTRACT  
 
The structure of a crystal complex of recombinant human immunodeficiency virus type 1 (HIV-1) protease with a peptide-mimetic inhibitor containing a dihydroxyethylene isostere insert replacing the scissile bond has been determined. The inhibitor is Noa-His-Hch psi [CH(OH)CH(OH)]Vam-Ile-Amp (U-75875), and its Ki for inhibition of the HIV-1 protease is < 1.0 nM (Noa = 1-naphthoxyacetyl, Hch = a hydroxy-modified form of cyclohexylalanine, Vam = a hydroxy-modified form of valine, Amp = 2-pyridylmethylamine). The structure of the complex has been refined to a crystallographic R factor of 0.169 at 2.0 A resolution by using restrained least-squares procedures. Root mean square deviations from ideality are 0.02 A and 2.4 degrees, for bond lengths and angles, respectively. The bound inhibitor diastereomer has the R configurations at both of the hydroxyl chiral carbon atoms. One of the diol hydroxyl groups is positioned such that it forms hydrogen bonds with both the active site aspartates, whereas the other interacts with only one of them. Comparison of this X-ray structure with a model-built structure of the inhibitor, published earlier, reveals similar positioning of the backbone atoms and of the side-chain atoms in the P2-P2' region, where the interaction with the protein is strongest. However, the X-ray structure and the model differ considerably in the location of the P3 and P3' end groups, and also in the positioning of the second of the two central hydroxyl groups. Reconstruction of the central portion of the model revealed the source of the hydroxyl discrepancy, which, when corrected, provided a P1-P1' geometry very close to that seen in the X-ray structure.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20490879 J.P.Yesudas, F.B.Sayyed, and C.H.Suresh (2011).
Analysis of structural water and CH···π interactions in HIV-1 protease and PTP1B complexes using a hydrogen bond prediction tool, HBPredicT.
  J Mol Model, 17, 401-413.  
20593466 M.Miller (2010).
The early years of retroviral protease crystal structures.
  Biopolymers, 94, 521-529.  
18988271 M.Arenas, M.C.Villaverde, and F.Sussman (2009).
Prediction and analysis of binding affinities for chemically diverse HIV-1 PR inhibitors by the modified SAFE_p approach.
  J Comput Chem, 30, 1229-1240.  
17986206 V.Namasivayam, and R.Günther (2007).
pso@autodock: a fast flexible molecular docking program based on Swarm intelligence.
  Chem Biol Drug Des, 70, 475-484.  
15507631 M.Prabu-Jeyabalan, E.A.Nalivaika, N.M.King, and C.A.Schiffer (2004).
Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease.
  J Virol, 78, 12446-12454.
PDB codes: 1tsq 1tsu
12675950 E.Jenwitheesuk, and R.Samudrala (2003).
Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations.
  BMC Struct Biol, 3, 2.  
12502847 M.Prabu-Jeyabalan, E.A.Nalivaika, N.M.King, and C.A.Schiffer (2003).
Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.
  J Virol, 77, 1306-1315.
PDB codes: 1mt7 1mt8 1mt9 1mtb 1n49
12005435 M.Prabu-Jeyabalan, E.Nalivaika, and C.A.Schiffer (2002).
Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes.
  Structure, 10, 369-381.
PDB codes: 1kj4 1kj7 1kjf 1kjg 1kjh
12324397 R.E.Georgescu, E.G.Alexov, and M.R.Gunner (2002).
Combining conformational flexibility and continuum electrostatics for calculating pK(a)s in proteins.
  Biophys J, 83, 1731-1748.  
11170214 B.Pillai, K.K.Kannan, and M.V.Hosur (2001).
1.9 A x-ray study shows closed flap conformation in crystals of tethered HIV-1 PR.
  Proteins, 43, 57-64.
PDB code: 1g6l
10388736 E.L.Mehler, and F.Guarnieri (1999).
A self-consistent, microenvironment modulated screened coulomb potential approximation to calculate pH-dependent electrostatic effects in proteins.
  Biophys J, 77, 3.  
10328309 S.Kurihara, T.Tsumuraya, and I.Fujii (1999).
Structure-based design of diaminopyranosides as a novel inhibitor core unit of HIV proteases.
  Bioorg Med Chem Lett, 9, 1179-1184.  
9485411 R.B.Rose, C.S.Craik, and R.M.Stroud (1998).
Domain flexibility in retroviral proteases: structural implications for drug resistant mutations.
  Biochemistry, 37, 2607-2621.
PDB code: 1az5
  9541388 T.J.Marrone, H.Resat, C.N.Hodge, C.H.Chang, and J.A.McCammon (1998).
Solvation studies of DMP323 and A76928 bound to HIV protease: analysis of water sites using grand canonical Monte Carlo simulations.
  Protein Sci, 7, 573-579.  
9346283 G.Lange-Savage, H.Berchtold, A.Liesum, K.H.Budt, A.Peyman, J.Knolle, J.Sedlacek, M.Fabry, and R.Hilgenfeld (1997).
Structure of HOE/BAY 793 complexed to human immunodeficiency virus (HIV-1) protease in two different crystal forms--structure/function relationship and influence of crystal packing.
  Eur J Biochem, 248, 313-322.
PDB codes: 1vij 1vik
9271500 G.S.Laco, C.Schalk-Hihi, J.Lubkowski, G.Morris, A.Zdanov, A.Olson, J.H.Elder, A.Wlodawer, and A.Gustchina (1997).
Crystal structures of the inactive D30N mutant of feline immunodeficiency virus protease complexed with a substrate and an inhibitor.
  Biochemistry, 36, 10696-10708.
PDB codes: 2fiv 3fiv
  8844837 A.Gustchina, J.Kervinen, D.J.Powell, A.Zdanov, J.Kay, and A.Wlodawer (1996).
Structure of equine infectious anemia virus proteinase complexed with an inhibitor.
  Protein Sci, 5, 1453-1465.
PDB code: 1fmb
8807858 C.N.Hodge, P.E.Aldrich, L.T.Bacheler, C.H.Chang, C.J.Eyermann, S.Garber, M.Grubb, D.A.Jackson, P.K.Jadhav, B.Korant, P.Y.Lam, M.B.Maurin, J.L.Meek, M.J.Otto, M.M.Rayner, C.Reid, T.R.Sharpe, L.Shum, D.L.Winslow, and S.Erickson-Viitanen (1996).
Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450.
  Chem Biol, 3, 301-314.
PDB code: 1dmp
8876160 F.McPhee, A.C.Good, I.D.Kuntz, and C.S.Craik (1996).
Engineering human immunodeficiency virus 1 protease heterodimers as macromolecular inhibitors of viral maturation.
  Proc Natl Acad Sci U S A, 93, 11477-11481.  
8552675 G.M.Verkhivker, and P.A.Rejto (1996).
A mean field model of ligand-protein interactions: implications for the structural assessment of human immunodeficiency virus type 1 protease complexes and receptor-specific binding.
  Proc Natl Acad Sci U S A, 93, 60-64.  
8756456 J.I.Yeh, A.Claiborne, and W.G.Hol (1996).
Structure of the native cysteine-sulfenic acid redox center of enterococcal NADH peroxidase refined at 2.8 A resolution.
  Biochemistry, 35, 9951-9957.
PDB code: 1joa
  8528086 A.Wallqvist, R.L.Jernigan, and D.G.Covell (1995).
A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-1-protease inhibitor design.
  Protein Sci, 4, 1881-1903.  
7613867 J.P.Priestle, A.Fässler, J.Rösel, M.Tintelnot-Blomley, P.Strop, and M.G.Grütter (1995).
Comparative analysis of the X-ray structures of HIV-1 and HIV-2 proteases in complex with CGP 53820, a novel pseudosymmetric inhibitor.
  Structure, 3, 381-389.
PDB codes: 1hih 1hii
8749849 L.A.Kuhn, C.A.Swanson, M.E.Pique, J.A.Tainer, and E.D.Getzoff (1995).
Atomic and residue hydrophilicity in the context of folded protein structures.
  Proteins, 23, 536-547.  
  7670378 V.Nauchitel, M.C.Villaverde, and F.Sussman (1995).
Solvent accessibility as a predictive tool for the free energy of inhibitor binding to the HIV-1 protease.
  Protein Sci, 4, 1356-1364.  
8397790 J.O.Hui, A.G.Tomasselli, I.M.Reardon, J.M.Lull, D.P.Brunner, C.S.Tomich, and R.L.Heinrikson (1993).
Large scale purification and refolding of HIV-1 protease from Escherichia coli inclusion bodies.
  J Protein Chem, 12, 323-327.  
8022862 W.Prusoff, T.S.Lin, A.Pivazyan, A.S.Sun, and E.Birks (1993).
Empirical and rational approaches for development of inhibitors of the human immunodeficiency virus--HIV-1.
  Pharmacol Ther, 60, 315-329.  
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.