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PDBsum entry 1k22
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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1k22

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
29 a.a. *
251 a.a. *
Ligands
ASP-PHE-GLU-GLU-
ILE-PRO-GLU-GLU-
TYS-LEU
NAG-NAG
MEL
Metals
_NA ×2
Waters ×239
* Residue conservation analysis
PDB id:
1k22
Name: Hydrolase/hydrolase inhibitor
Title: Human thrombin-inhibitor complex
Structure: Prothrombin. Chain: l. Fragment: thrombin light chain, residues 323-363. Synonym: alpha-thrombin, coagulation factor ii. Prothrombin. Chain: h. Fragment: thrombin heavy chain, residues 364-622. Synonym: alpha-thrombin, coagulation factor ii. Hirudin variant-2.
Source: Homo sapiens. Human. Organism_taxid: 9606. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
Biol. unit: Trimer (from PQS)
Resolution:
1.93Å     R-factor:   0.197     R-free:   0.214
Authors: M.T.Stubbs,D.Musil
Key ref:
F.Dullweber et al. (2001). Factorising ligand affinity: a combined thermodynamic and crystallographic study of trypsin and thrombin inhibition. J Mol Biol, 313, 593-614. PubMed id: 11676542 DOI: 10.1006/jmbi.2001.5062
Date:
26-Sep-01     Release date:   08-May-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
29 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
251 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains L, H: E.C.3.4.21.5  - thrombin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

 

 
DOI no: 10.1006/jmbi.2001.5062 J Mol Biol 313:593-614 (2001)
PubMed id: 11676542  
 
 
Factorising ligand affinity: a combined thermodynamic and crystallographic study of trypsin and thrombin inhibition.
F.Dullweber, M.T.Stubbs, D.Musil, J.Stürzebecher, G.Klebe.
 
  ABSTRACT  
 
The binding of a series of low molecular weight ligands towards trypsin and thrombin has been studied by isothermal titration calorimetry and protein crystallography. In a series of congeneric ligands, surprising changes of protonation states occur and are overlaid on the binding process. They result from induced pK(a) shifts depending on the local environment experienced by the ligand and protein functional groups in the complex (induced dielectric fit). They involve additional heat effects that must be corrected before any conclusion on the binding enthalpy (DeltaH) and entropy (DeltaS) can be drawn. After correction, trends in both contributions can be interpreted in structural terms with respect to the hydrogen bond inventory or residual ligand motions. For all inhibitors studied, a strong negative heat capacity change (DeltaC(p)) is detected, thus binding becomes more exothermic and entropically less favourable with increasing temperature. Due to a mutual compensation, Gibbs free energy remains virtually unchanged. The strong negative DeltaC(p) value cannot solely be explained by the removal of hydrophobic surface portions of the protein or ligand from water exposure. Additional contributions must be considered, presumably arising from modulations of the local water structure, changes in vibrational modes or other ordering parameters. For thrombin, smaller negative DeltaC(p) values are observed for ligand binding in the presence of sodium ions compared to the other alkali ions, probably due to stabilising effects on the protein or changes in the bound water structure.
 
  Selected figure(s)  
 
Figure 8.
Figure 8. Alignment of inhibitors 1b (blue) and 2 (white). Trypsin shown by its solvent accessible surface. The inhibitors were superimposed using the atoms of amino acid residues His57, Asp102, Asp189 and Ser195 of trypsin or thrombin, respectively. Arrow indicates the location of the carboxylic groups. 		Figure 12.
Figure 12. Alignment of inhibitors 2 (white) and 3 (orange). Human a-thrombin is shown by its solvent accessible surface. The inhibitors were superimposed using the atoms of amino acid residues His57, Asp102, Asp189 and Ser195 of trypsin or thrombin, respectively. Arrows indicate the location of the carboxylic groups.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2001, 313, 593-614) copyright 2001.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21058298 M.S.Park, C.Gao, and H.A.Stern (2011).
Estimating binding affinities by docking/scoring methods using variable protonation states.
  Proteins, 79, 304-314.  
20223699 A.G.Coyne, D.E.Scott, and C.Abell (2010).
Drugging challenging targets using fragment-based approaches.
  Curr Opin Chem Biol, 14, 299-307.  
20345171 C.Bissantz, B.Kuhn, and M.Stahl (2010).
A medicinal chemist's guide to molecular interactions.
  J Med Chem, 53, 5061-5084.  
19960014 J.E.Ladbury, G.Klebe, and E.Freire (2010).
Adding calorimetric data to decision making in lead discovery: a hot tip.
  Nat Rev Drug Discov, 9, 23-27.  
  20186976 N.Singh, and A.Warshel (2010).
Absolute binding free energy calculations: on the accuracy of computational scoring of protein-ligand interactions.
  Proteins, 78, 1705-1723.  
  20186973 N.Singh, and A.Warshel (2010).
A comprehensive examination of the contributions to the binding entropy of protein-ligand complexes.
  Proteins, 78, 1724-1735.  
20148287 O.Nicolotti, I.Giangreco, T.F.Miscioscia, M.Convertino, F.Leonetti, L.Pisani, and A.Carotti (2010).
Screening of benzamidine-based thrombin inhibitors via a linear interaction energy in continuum electrostatics model.
  J Comput Aided Mol Des, 24, 117-129.  
19368882 D.L.Mobley, and K.A.Dill (2009).
Binding of small-molecule ligands to proteins: "what you see" is not always "what you get".
  Structure, 17, 489-498.  
19162547 M.Cugno, A.Zanichelli, F.Foieni, S.Caccia, and M.Cicardi (2009).
C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress.
  Trends Mol Med, 15, 69-78.  
19435349 X.Li, X.He, B.Wang, and K.Merz (2009).
Conformational variability of benzamidinium-based inhibitors.
  J Am Chem Soc, 131, 7742-7754.  
19725878 Y.Uesugi, H.Usuki, M.Iwabuchi, and T.Hatanaka (2009).
The role of Tyr71 in Streptomyces trypsin on the recognition mechanism of structural protein substrates.
  FEBS J, 276, 5634-5646.  
18498103 D.C.Bas, D.M.Rogers, and J.H.Jensen (2008).
Very fast prediction and rationalization of pKa values for protein-ligand complexes.
  Proteins, 73, 765-783.  
18384086 I.Reulecke, G.Lange, J.Albrecht, R.Klein, and M.Rarey (2008).
Towards an integrated description of hydrogen bonding and dehydration: decreasing false positives in virtual screening with the HYDE scoring function.
  ChemMedChem, 3, 885-897.  
17680772 F.V.Grigoriev, S.V.Luschekina, A.N.Romanov, V.B.Sulimov, and E.A.Nikitina (2007).
Computation of entropy contribution to protein-ligand binding free energy.
  Biochemistry (Mosc), 72, 785-792.  
17443320 G.Bruylants, R.Wintjens, Y.Looze, C.Redfield, and K.Bartik (2007).
Protonation linked equilibria and apparent affinity constants: the thermodynamic profile of the alpha-chymotrypsin-proflavin interaction.
  Eur Biophys J, 37, 11-18.  
17013633 G.Mlinsek, M.Oblak, M.Hodoscek, and T.Solmajer (2007).
Thrombin inhibitors with novel P1 binding pocket functionality: free energy of binding analysis.
  J Mol Model, 13, 247-254.  
17372355 M.Sherawat, P.Kaur, M.Perbandt, C.Betzel, W.A.Slusarchyk, G.S.Bisacchi, C.Chang, B.L.Jacobson, H.M.Einspahr, and T.P.Singh (2007).
Structure of the complex of trypsin with a highly potent synthetic inhibitor at 0.97 A resolution.
  Acta Crystallogr D Biol Crystallogr, 63, 500-507.
PDB code: 2ayw
16299076 B.Nguyen, J.Stanek, and W.D.Wilson (2006).
Binding-linked protonation of a DNA minor-groove agent.
  Biophys J, 90, 1319-1328.  
16374786 J.Fokkens, and G.Klebe (2006).
A simple protocol to estimate differences in protein binding affinity for enantiomers without prior resolution of racemates.
  Angew Chem Int Ed Engl, 45, 985-989.
PDB codes: 1y3v 1y3w 1y3x 1y3y 1yp9 1ype 1ypg 1ypj 1ypk
16927370 P.Czodrowski, I.Dramburg, C.A.Sotriffer, and G.Klebe (2006).
Development, validation, and application of adapted PEOE charges to estimate pKa values of functional groups in protein-ligand complexes.
  Proteins, 65, 424-437.  
16344948 S.Cotesta, and M.Stahl (2006).
The environment of amide groups in protein-ligand complexes: H-bonds and beyond.
  J Mol Model, 12, 436-444.  
15937115 D.Riester, F.Wirsching, G.Salinas, M.Keller, M.Gebinoga, S.Kamphausen, C.Merkwirth, R.Goetz, M.Wiesenfeldt, J.Stürzebecher, W.Bode, R.Friedrich, M.Thürk, and A.Schwienhorst (2005).
Thrombin inhibitors identified by computer-assisted multiparameter design.
  Proc Natl Acad Sci U S A, 102, 8597-8602.  
15150279 A.Schweinitz, T.Steinmetzer, I.J.Banke, M.J.Arlt, A.Stürzebecher, O.Schuster, A.Geissler, H.Giersiefen, E.Zeslawska, U.Jacob, A.Krüger, and J.Stürzebecher (2004).
Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents.
  J Biol Chem, 279, 33613-33622.
PDB codes: 1sc8 1vj9 1vja
15557258 M.J.Lachenmann, J.E.Ladbury, X.Qian, K.Huang, R.Singh, and M.A.Weiss (2004).
Solvation and the hidden thermodynamics of a zinc finger probed by nonstandard repair of a protein crevice.
  Protein Sci, 13, 3115-3126.
PDB code: 1xrz
12952957 Z.Zavala-Ruiz, E.J.Sundberg, J.D.Stone, D.B.DeOliveira, I.C.Chan, J.Svendsen, R.A.Mariuzza, and L.J.Stern (2003).
Exploration of the P6/P7 region of the peptide-binding site of the human class II major histocompatability complex protein HLA-DR1.
  J Biol Chem, 278, 44904-44912.
PDB code: 1pyw
12210999 I.Luque, and E.Freire (2002).
Structural parameterization of the binding enthalpy of small ligands.
  Proteins, 49, 181-190.  
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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