PDBsum entry 1c1u

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protein ligands metals Protein-protein interface(s) links
Blood clotting/hydrolase inhibitor PDB id
Protein chains
36 a.a. *
252 a.a. *
11 a.a. *
Waters ×864
* Residue conservation analysis
PDB id:
Name: Blood clotting/hydrolase inhibitor
Title: Recruiting zinc to mediate potent, specific inhibition of se proteases
Structure: Alpha thrombin. Chain: l. Fragment: light chain. Alpha thrombin. Chain: h. Fragment: heavy chain. Other_details: complexed with (5-amidino-2-benzimidazolyl)( benzimidazolyl)methane. Acetyl hirudin.
Source: Homo sapiens. Human. Organism_taxid: 9606. Synthetic: yes. Hirudo medicinalis. Organism_taxid: 6421
Biol. unit: Trimer (from PQS)
1.75Å     R-factor:   0.206     R-free:   0.235
Authors: B.A.Katz,C.Luong
Key ref:
B.A.Katz et al. (1998). Design of potent selective zinc-mediated serine protease inhibitors. Nature, 391, 608-612. PubMed id: 9468142 DOI: 10.1038/35422
21-Jul-99     Release date:   26-Jul-00    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
622 a.a.
36 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
622 a.a.
252 a.a.
Protein chain
Pfam   ArchSchema ?
P28504  (HIR2_HIRME) -  Hirudin-2
65 a.a.
11 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains L, H: E.C.  - Thrombin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     blood coagulation   2 terms 
  Biochemical function     catalytic activity     3 terms  


DOI no: 10.1038/35422 Nature 391:608-612 (1998)
PubMed id: 9468142  
Design of potent selective zinc-mediated serine protease inhibitors.
B.A.Katz, J.M.Clark, J.S.Finer-Moore, T.E.Jenkins, C.R.Johnson, M.J.Ross, C.Luong, W.R.Moore, R.M.Stroud.
Many serine proteases are targets for therapeutic intervention because they often play key roles in disease. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion.
  Selected figure(s)  
Figure 1.
Figure 1 (2|F[o]| - |F[c]|), [c] map superimposed on the structure of trypsin-keto-BABIM-Zn2+, pH 8.2.
Figure 2.
Figure 2 Superposition of trypsin-BABIM-Zn2+ onto keto-BABIM-Zn2+. In the trypsin-BABIM-Zn2+ structure, carbons are green, oxygens red, nitrogens blue and sulphurs yellow. In the trypsin-keto-BABIM-Zn2+ structure, carbons are light blue, oxygens orange, nitrogens rose, and sulphurs yellow.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1998, 391, 608-612) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19889537 S.C.Chai, and Q.Z.Ye (2009).
Metal-mediated inhibition is a viable approach for inhibiting cellular methionine aminopeptidase.
  Bioorg Med Chem Lett, 19, 6862-6864.  
18083072 A.K.Satheesh Babu, M.A.Vijayalakshmi, G.J.Smith, and K.C.Chadha (2008).
Thiophilic-interaction chromatography of enzymatically active tissue prostate-specific antigen (T-PSA) and its modulation by zinc ions.
  J Chromatogr B Analyt Technol Biomed Life Sci, 861, 227-235.  
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.  
17191291 A.Di Fenza, A.Heine, U.Koert, and G.Klebe (2007).
Understanding Binding Selectivity toward Trypsin and Factor Xa: the Role of Aromatic Interactions.
  ChemMedChem, 2, 297-308.
PDB codes: 1y59 1y5a 1y5b 1y5u
17498057 G.H.Caughey (2007).
Mast cell tryptases and chymases in inflammation and host defense.
  Immunol Rev, 217, 141-154.  
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
16827563 G.E.Boldt, J.P.Kennedy, M.S.Hixon, L.A.McAllister, J.T.Barbieri, S.Tzipori, and K.D.Janda (2006).
Synthesis, characterization and development of a high-throughput methodology for the discovery of botulinum neurotoxin a inhibitors.
  J Comb Chem, 8, 513-521.  
16640553 J.Hallgren, and G.Pejler (2006).
Biology of mast cell tryptase. An inflammatory mediator.
  FEBS J, 273, 1871-1895.  
16045357 B.S.Sandanaraj, D.R.Vutukuri, J.M.Simard, A.Klaikherd, R.Hong, V.M.Rotello, and S.Thayumanavan (2005).
Noncovalent modification of chymotrypsin surface using an amphiphilic polymer scaffold: implications in modulating protein function.
  J Am Chem Soc, 127, 10693-10698.  
15706577 R.Paulini, K.Müller, and F.Diederich (2005).
Orthogonal multipolar interactions in structural chemistry and biology.
  Angew Chem Int Ed Engl, 44, 1788-1805.  
15880695 R.Schiffmann, A.Heine, G.Klebe, and C.D.Klein (2005).
Metal ions as cofactors for the binding of inhibitors to methionine aminopeptidase: a critical view of the relevance of in vitro metalloenzyme assays.
  Angew Chem Int Ed Engl, 44, 3620-3623.
PDB code: 1yvm
15250038 C.A.Kontogiorgis, and D.Hadjipavlou-Litina (2004).
Current trends in quantitative structure activity relationships on FXa inhibitors: evaluation and comparative analysis.
  Med Res Rev, 24, 687-747.  
15044735 H.K.Leiros, B.O.Brandsdal, O.A.Andersen, V.Os, I.Leiros, R.Helland, J.Otlewski, N.P.Willassen, and A.O.Smalås (2004).
Trypsin specificity as elucidated by LIE calculations, X-ray structures, and association constant measurements.
  Protein Sci, 13, 1056-1070.
PDB codes: 1utj 1utk 1utl 1utm 1utn 1uto 1utp 1utq
15255189 N.M.Barros, I.L.Tersariol, M.L.Oliva, M.S.Araújo, C.A.Sampaio, L.Juliano, and G.da Motta (2004).
High molecular weight kininogen as substrate for cathepsin B.
  Biol Chem, 385, 551-555.  
12808236 E.Toyota, H.Sekizaki, K.Itoh, and K.Tanizawa (2003).
Synthesis and evaluation of guanidine-containing Schiff base copper(II), zinc(II), and iron(III) chelates as trypsin inhibitors.
  Chem Pharm Bull (Tokyo), 51, 625-629.  
12437105 J.A.Krauser, J.Potempa, J.Travis, and J.C.Powers (2002).
Inhibition of arginine gingipains (RgpB and HRgpA) with benzamidine inhibitors: zinc increases inhibitory potency.
  Biol Chem, 383, 1193-1198.  
12146945 S.Eswaramoorthy, D.Kumaran, and S.Swaminathan (2002).
A novel mechanism for Clostridium botulinum neurotoxin inhibition.
  Biochemistry, 41, 9795-9802.
PDB codes: 1g9a 1g9b 1g9c 1g9d
11353508 R.Nguyen, and I.Huc (2001).
Using an Enzyme's Active Site To Template Inhibitors This work was supported by the Centre National de la Recherche Scientifique and by the Ecole Polytechnique (predoctoral fellowship to R.N.). We thank Prof. Jean-Marie Lehn for stimulating discussions.
  Angew Chem Int Ed Engl, 40, 1774-1776.  
11668569 S.Valente, M.Gobbo, G.Licini, A.Scarso, and P.Scrimin (2001).
Allosteric Regulation of an HIV-1 Protease Inhibitor by Zn(II) Ions This work was funded by MURST (COFIN2000-MM03194891). We thank Prof. P. Tecilla (U. Trieste) for valuable comments.
  Angew Chem Int Ed Engl, 40, 3899-3902.  
10813384 D.R.Abendschein, P.K.Baum, D.J.Martin, R.Vergona, J.Post, G.Rumennik, M.E.Sullivan, P.R.Eisenberg, and D.R.Light (2000).
Effects of ZK-807834, a novel inhibitor of factor Xa, on arterial and venous thrombosis in rabbits.
  J Cardiovasc Pharmacol, 35, 796-805.  
10769136 J.W.Janc, J.M.Clark, R.L.Warne, K.C.Elrod, B.A.Katz, and W.R.Moore (2000).
A novel approach to serine protease inhibition: kinetic characterization of inhibitors whose potencies and selectivities are dramatically enhanced by Zinc(II).
  Biochemistry, 39, 4792-4800.  
10825730 N.A.Meanwell, and M.Krystal (2000).
Respiratory syncytial virus: recent progress towards the discovery of effective prophylactic and therapeutic agents.
  Drug Discov Today, 5, 241-252.  
11012675 P.Wu, J.Leinonen, E.Koivunen, H.Lankinen, and U.H.Stenman (2000).
Identification of novel prostate-specific antigen-binding peptides modulating its enzyme activity.
  Eur J Biochem, 267, 6212-6220.  
10535920 C.E.Elling, K.Thirstrup, B.Holst, and T.W.Schwartz (1999).
Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor.
  Proc Natl Acad Sci U S A, 96, 12322-12327.  
10500112 C.P.Sommerhoff, W.Bode, P.J.Pereira, M.T.Stubbs, J.Stürzebecher, G.P.Piechottka, G.Matschiner, and A.Bergner (1999).
The structure of the human betaII-tryptase tetramer: fo(u)r better or worse.
  Proc Natl Acad Sci U S A, 96, 10984-10991.  
10468550 I.D.Kuntz, K.Chen, K.A.Sharp, and P.A.Kollman (1999).
The maximal affinity of ligands.
  Proc Natl Acad Sci U S A, 96, 9997.  
10476865 M.L.López-Rodríguez, A.Viso, B.Benhamú, J.L.Rominguera, and M.Murcia (1999).
Synthesis of new (benzimidazolyl)piperazines with affinity for the 5-HT1A receptor via Pd(0) amination of bromobenzimidazoles.
  Bioorg Med Chem Lett, 9, 2339-2342.  
  9568894 B.A.Katz, B.Liu, M.Barnes, and E.B.Springman (1998).
Crystal structure of recombinant human tissue kallikrein at 2.0 A resolution.
  Protein Sci, 7, 875-885.  
9653544 H.H.Thorp (1998).
Bioinorganic chemistry and drug design: here comes zinc again.
  Chem Biol, 5, R125-R127.  
9836602 S.R.Presnell, G.S.Patil, C.Mura, K.M.Jude, J.M.Conley, J.A.Bertrand, C.M.Kam, J.C.Powers, and L.D.Williams (1998).
Oxyanion-mediated inhibition of serine proteases.
  Biochemistry, 37, 17068-17081.
PDB codes: 1bju 1bjv
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.