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Hydrolase PDB id
1bxo
Jmol
Contents
Protein chain
323 a.a. *
Ligands
MAN ×2
SO4
PP7
GOL ×2
Waters ×543
* Residue conservation analysis
PDB id:
1bxo
Name: Hydrolase
Title: Acid proteinase (penicillopepsin) (E.C.3.4.23.20) complex wi phosphonate inhibitor: methyl cyclo[(2s)-2-[[(1r)-1-(n-(l-n methylbutanoyl)valyl-l-aspartyl)amino)-3-methylbut yl] hydroxyphosphinyloxy]-3-(3-aminomethyl) phenylpropanoate
Structure: Protein (penicillopepsin). Chain: a. Ec: 3.4.23.20
Source: Penicillium janthinellum. Organism_taxid: 5079
Biol. unit: Dimer (from PQS)
Resolution:
0.95Å     R-factor:   0.100     R-free:   0.125
Authors: A.R.Khan,J.C.Parrish,M.E.Fraser,W.W.Smith,P.A.Bartlett,M.N.G
Key ref:
A.R.Khan et al. (1998). Lowering the entropic barrier for binding conformationally flexible inhibitors to enzymes. Biochemistry, 37, 16839-16845. PubMed id: 9836576 DOI: 10.1021/bi9821364
Date:
07-Oct-98     Release date:   14-Oct-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00798  (PENP_PENJA) -  Penicillopepsin
Seq:
Struc: 		323 a.a.
323 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.23.20  - Penicillopepsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of proteins with broad specificity similar to that of pepsin A, preferring hydrophobic residues at P1 and P1', but also cleaving 20-Gly-|-Glu-21 in the B chain of insulin. Clots milk, and activates trypsinogen.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     hydrolase activity     3 terms  

 

 
DOI no: 10.1021/bi9821364 Biochemistry 37:16839-16845 (1998)
PubMed id: 9836576  
 
 
Lowering the entropic barrier for binding conformationally flexible inhibitors to enzymes.
A.R.Khan, J.C.Parrish, M.E.Fraser, W.W.Smith, P.A.Bartlett, M.N.James.
 
  ABSTRACT  
 
The design of inhibitors with enhanced potency against proteolytic enzymes has many applications for the treatment of human diseases. In addition to the optimization of chemical interactions between the enzyme and inhibitor, the binding affinity can be increased by constraining the inhibitor to the conformation that is recognized by the enzyme, thus lowering the entropic barrier to complex formation. We have structurally characterized the complexes of a macrocyclic pentapeptide inhibitor and its acyclic analogue with penicillopepsin, an aspartic proteinase, to study the effect of conformational constraint on the binding affinity. The phosphonate-based macrocycle PPi4 (Ki = 0.10 nM) is covalently linked at the P2-Asn and P1'-Phe side chains [nomenclature of Schechter and Berger, Biochim. Biophys. Res. Commun. (1967) 27, via an amide bond, relative to the acyclic compound PPi3 (Ki = 42 nM). Comparisons of the high-resolution crystal structures of PPi4-penicillopepsin (0.95 A) and PPi3-penicillopepsin (1.45 A) reveal that the conformations of the inhibitors and their interactions with the enzyme are similar. The 420-fold increase in the binding affinity of PPi4 is attributed to a reduction in its conformational flexibility, thus providing the first rigorous measure of the entropic contribution to the binding energy in a protein-ligand complex and stressing the advantages of the design strategy.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21369577 A.S.Evitt, and R.J.Cox (2011).
Synthesis and evaluation of conformationally restricted inhibitors of aspartate semialdehyde dehydrogenase.
  Mol Biosyst, 7, 1564-1575.  
20213667 V.Giménez-Oya, O.Villacañas, C.Obiol-Pardo, M.Antolin-Llovera, J.Rubio-Martinez, and S.Imperial (2011).
Design of novel ligands of CDP-methylerythritol kinase by mimicking direct protein-protein and solvent-mediated interactions.
  J Mol Recognit, 24, 71-80.  
20944243 J.H.Clements, J.E.DeLorbe, A.P.Benfield, and S.F.Martin (2010).
Binding of flexible and constrained ligands to the Grb2 SH2 domain: structural effects of ligand preorganization.
  Acta Crystallogr D Biol Crystallogr, 66, 1101-1115.  
19539345 G.Ye, A.D.Schuler, Y.Ahmadibeni, J.R.Morgan, A.Faruqui, K.Huang, G.Sun, J.A.Zebala, and K.Parang (2009).
Synthesis and evaluation of phosphopeptides containing iminodiacetate groups as binding ligands of the Src SH2 domain.
  Bioorg Chem, 37, 133-142.  
19863063 S.Puthenveetil, D.S.Liu, K.A.White, S.Thompson, and A.Y.Ting (2009).
Yeast display evolution of a kinetically efficient 13-amino acid substrate for lipoic acid ligase.
  J Am Chem Soc, 131, 16430-16438.  
19435349 X.Li, X.He, B.Wang, and K.Merz (2009).
Conformational variability of benzamidinium-based inhibitors.
  J Am Chem Soc, 131, 7742-7754.  
18675276 A.S.Nascimento, S.Krauchenco, A.M.Golubev, A.Gustchina, A.Wlodawer, and I.Polikarpov (2008).
Statistical coupling analysis of aspartic proteinases based on crystal structures of the Trichoderma reesei enzyme and its complex with pepstatin A.
  J Mol Biol, 382, 763-778.
PDB codes: 3c9x 3c9y 3emy
18335423 D.G.Udugamasooriya, and M.R.Spaller (2008).
Conformational constraint in protein ligand design and the inconsistency of binding entropy.
  Biopolymers, 89, 653-667.  
17001728 A.P.Benfield, M.G.Teresk, H.R.Plake, J.E.DeLorbe, L.E.Millspaugh, and S.F.Martin (2006).
Ligand preorganization may be accompanied by entropic penalties in protein-ligand interactions.
  Angew Chem Int Ed Engl, 45, 6830-6835.
PDB codes: 2huw 2huy 3c7i
16734454 F.P.Seebeck, and J.W.Szostak (2006).
Ribosomal synthesis of dehydroalanine-containing peptides.
  J Am Chem Soc, 128, 7150-7151.  
16280623 C.Chennubhotla, A.J.Rader, L.W.Yang, and I.Bahar (2005).
Elastic network models for understanding biomolecular machinery: from enzymes to supramolecular assemblies.
  Phys Biol, 2, S173-S180.  
16116659 L.Mercklé, A.de Andrés-Gómez, B.Dick, R.J.Cox, and C.R.Godfrey (2005).
A fragment-based approach to understanding inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase.
  Chembiochem, 6, 1866-1874.  
15939021 L.W.Yang, and I.Bahar (2005).
Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes.
  Structure, 13, 893-904.  
15020763 C.Y.Kim, H.Quarsten, E.Bergseng, C.Khosla, and L.M.Sollid (2004).
Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease.
  Proc Natl Acad Sci U S A, 101, 4175-4179.
PDB code: 1s9v
15386268 Y.S.Tsantrizos (2004).
The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN 2061--from the NMR tube to the clinic.
  Biopolymers, 76, 309-323.  
  11514229 C.P.Scott, E.Abel-Santos, A.D.Jones, and S.J.Benkovic (2001).
Structural requirements for the biosynthesis of backbone cyclic peptide libraries.
  Chem Biol, 8, 801-815.  
11714911 N.S.Andreeva, and L.D.Rumsh (2001).
Analysis of crystal structures of aspartic proteinases: on the role of amino acid residues adjacent to the catalytic site of pepsin-like enzymes.
  Protein Sci, 10, 2439-2450.  
11223515 S.Teixeira, L.Lo Leggio, R.Pickersgill, and C.Cardin (2001).
Anisotropic refinement of the structure of Thermoascus aurantiacus xylanase I.
  Acta Crystallogr D Biol Crystallogr, 57, 385-392.
PDB code: 1fxm
11418762 S.W.Cho, N.Kim, M.U.Choi, and W.Shin (2001).
Structure of aspergillopepsin I from Aspergillus phoenicis: variations of the S1'-S2 subsite in aspartic proteinases.
  Acta Crystallogr D Biol Crystallogr, 57, 948-956.
PDB code: 1ibq
10828360 B.M.Goldstein, and T.D.Colby (2000).
Conformational constraints in NAD analogs: implications for dehydrogenase binding and specificity.
  Adv Enzyme Regul, 40, 405-426.  
10329772 E.A.Merritt (1999).
Expanding the model: anisotropic displacement parameters in protein structure refinement.
  Acta Crystallogr D Biol Crystallogr, 55, 1109-1117.  
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.