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

 

 

 

 

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Contents
Protein chains
99 a.a. *
Ligands
PO4 ×4
ACT ×2
MUU
Waters ×169
* Residue conservation analysis
PDB id:
2psu
Name: Hydrolase
Title: Crystal structure of wild type HIV-1 protease in complex with carb- ad37
Structure: Protease. Chain: a, b. Engineered: yes. Mutation: yes
Source: Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: sf2. Gene: pol. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.93Å     R-factor:   0.162     R-free:   0.198
Authors: C.A.Schiffer,M.N.L.Nalam
Key ref: S.Chellappan et al. (2007). Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis. Chem Biol Drug Des, 69, 298-313. PubMed id: 17539822
Date:
07-May-07     Release date:   05-Jun-07    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
O38723  (O38723_9HIV1) -  Protease (Fragment) from Human immunodeficiency virus 1
Seq:
Struc: 		99 a.a.
99 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 

 
Chem Biol Drug Des 69:298-313 (2007)
PubMed id: 17539822  
 
 
Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis.
S.Chellappan, G.S.Kiran Kumar Reddy, A.Ali, M.N.Nalam, S.G.Anjum, H.Cao, V.Kairys, M.X.Fernandes, M.D.Altman, B.Tidor, T.M.Rana, C.A.Schiffer, M.K.Gilson.
 
  ABSTRACT  
 
There is a clinical need for HIV protease inhibitors that can evade resistance mutations. One possible approach to designing such inhibitors relies upon the crystallographic observation that the substrates of HIV protease occupy a rather constant region within the binding site. In particular, it has been hypothesized that inhibitors which lie within this region will tend to resist clinically relevant mutations. The present study offers the first prospective evaluation of this hypothesis, via computational design of inhibitors predicted to conform to the substrate envelope, followed by synthesis and evaluation against wild-type and mutant proteases, as well as structural studies of complexes of the designed inhibitors with HIV protease. The results support the utility of the substrate envelope hypothesis as a guide to the design of robust protease inhibitors.
 

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.  
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
21084633 K.P.Romano, A.Ali, W.E.Royer, and C.A.Schiffer (2010).
Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding.
  Proc Natl Acad Sci U S A, 107, 20986-20991.
PDB codes: 3m5l 3m5m 3m5n 3m5o
  21172023 M.C.Méndez-Ortega, S.Restrepo, L.M.Rodríguez-R, I.Pérez, J.C.Mendoza, A.P.Martínez, R.Sierra, and G.J.Rey-Benito (2010).
An RNAi in silico approach to find an optimal shRNA cocktail against HIV-1.
  Virol J, 7, 369.  
20237088 M.N.Nalam, A.Ali, M.D.Altman, G.S.Reddy, S.Chellappan, V.Kairys, A.Ozen, H.Cao, M.K.Gilson, B.Tidor, T.M.Rana, and C.A.Schiffer (2010).
Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance.
  J Virol, 84, 5368-5378.
PDB codes: 3gi4 3gi5 3gi6
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
19193159 R.N.Jorissen, G.S.Reddy, A.Ali, M.D.Altman, S.Chellappan, S.G.Anjum, B.Tidor, C.A.Schiffer, T.M.Rana, and M.K.Gilson (2009).
Additivity in the analysis and design of HIV protease inhibitors.
  J Med Chem, 52, 737-754.  
20354588 R.V.Swift, and R.E.Amaro (2009).
Discovery and design of DNA and RNA ligase inhibitors in infectious microorganisms.
  Expert Opin Drug Discov, 4, 1281-1294.  
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.  
19703025 V.Kairys, M.K.Gilson, V.Lather, C.A.Schiffer, and M.X.Fernandes (2009).
Toward the design of mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis.
  Chem Biol Drug Des, 74, 234-245.  
19373036 M.N.Nalam, and C.A.Schiffer (2008).
New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors.
  Curr Opin HIV AIDS, 3, 642-646.  
18481899 N.Kaushik-Basu, A.Basu, and D.Harris (2008).
Peptide inhibition of HIV-1: current status and future potential.
  BioDrugs, 22, 161-175.  
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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