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PDBsum entry 1lhf
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protein ligands Protein-protein interface(s) links
Complex (serine protease/inhibitor) PDB id
1lhf

 

 

 

 

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Contents
Protein chains
26 a.a. *
249 a.a. *
Ligands
GLY-ASP-PHE-GLU-
GLU-ILE-PRO
DI4
Waters ×96
* Residue conservation analysis
PDB id:
1lhf
Name: Complex (serine protease/inhibitor)
Title: Human alpha-thrombin complexed with ac-(d)phe-pro-boro-homolys-oh
Structure: Alpha-thrombin. Chain: l. Alpha-thrombin. Chain: h. Hirudin. Chain: i. Fragment: residues 54 - 65. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Tissue: blood. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
Biol. unit: Not given
Resolution:
2.40Å     R-factor:   0.212    
Authors: P.C.Weber,S.L.Lee,F.A.Lewandowski,M.C.Schadt,C.H.Chang,C.A.Kettner
Key ref:
P.C.Weber et al. (1995). Kinetic and crystallographic studies of thrombin with Ac-(D)Phe-Pro-boroArg-OH and its lysine, amidine, homolysine, and ornithine analogs. Biochemistry, 34, 3750-3757. PubMed id: 7893672
Date:
27-Dec-94     Release date:   08-Nov-96    
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.
26 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
249 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.

 

 
Biochemistry 34:3750-3757 (1995)
PubMed id: 7893672  
 
 
Kinetic and crystallographic studies of thrombin with Ac-(D)Phe-Pro-boroArg-OH and its lysine, amidine, homolysine, and ornithine analogs.
P.C.Weber, S.L.Lee, F.A.Lewandowski, M.C.Schadt, C.W.Chang, C.A.Kettner.
 
  ABSTRACT  
 
The X-ray crystallographic structure of Ac-(D)Phe-Pro-boroArg-OH [DuP714, Ki = 0.04 nM; Kettner, C., Mersinger, L., & Knabb, R. (1990) J. Biol. Chem. 265, 18289] complexed with human alpha-thrombin shows the boron atom covalently bonded to the side-chain oxygen of the active site serine, Ser195. The boron adopts a nearly tetrahedral geometry, and the boronic acid forms a set of interactions with the protein that mimic the tetrahedral transition state of serine proteases. Contributions of the arginine side chain to inhibitor affinity were examined by synthesis of the ornithine, lysine, homolysine, and amidine analogs of DuP714. The basic groups interact with backbone carbonyl groups, water molecules, and an aspartic acid side chain (Asp189) located in the thrombin S1 specificity pocket. The variation in inhibition constant by 3 orders of magnitude appears to reflect differences in the energetics of interactions made with thrombin and differences in ligand flexibility in solution.(ABSTRACT TRUNCATED AT 250 WORDS)
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20077463 N.Schaschke, and C.P.Sommerhoff (2010).
Upgrading a Natural Product: Inhibition of Human beta-Tryptase by Cyclotheonamide Analogues.
  ChemMedChem, 5, 367-370.  
16990937 D.Pearson, and A.D.Abell (2006).
Photoswitch inhibitors of alpha-chymotrypsin--increased substitution and peptidic character in peptidomimetic boronate esters.
  Org Biomol Chem, 4, 3618-3625.  
16531229 M.Groll, C.R.Berkers, H.L.Ploegh, and H.Ovaa (2006).
Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome.
  Structure, 14, 451-456.
PDB code: 2f16
16001954 C.S.Mitsiades, N.Mitsiades, T.Hideshima, P.G.Richardson, and K.C.Anderson (2005).
Proteasome inhibition as a therapeutic strategy for hematologic malignancies.
  Expert Rev Anticancer Ther, 5, 465-476.  
15389730 S.Srivastava, L.N.Goswami, and D.K.Dikshit (2005).
Progress in the design of low molecular weight thrombin inhibitors.
  Med Res Rev, 25, 66-92.  
15144949 J.Adams (2004).
The development of proteasome inhibitors as anticancer drugs.
  Cancer Cell, 5, 417-421.  
12009902 M.R.Harpel, K.Y.Horiuchi, Y.Luo, L.Shen, W.Jiang, D.J.Nelson, K.C.Rogers, C.P.Decicco, and R.A.Copeland (2002).
Mutagenesis and mechanism-based inhibition of Streptococcus pyogenes Glu-tRNAGln amidotransferase implicate a serine-based glutaminase site.
  Biochemistry, 41, 6398-6407.  
11550073 M.P.Groziak (2001).
Boron therapeutics on the horizon.
  Am J Ther, 8, 321-328.  
11016878 J.Deadman (2000).
Proteinase inhibitors and activators strategic targets for therapeutic intervention.
  J Pept Sci, 6, 421-431.  
10713516 R.Krishnan, I.Mochalkin, R.Arni, and A.Tulinsky (2000).
Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1.
  Acta Crystallogr D Biol Crystallogr, 56, 294-303.
PDB codes: 1c4u 1c4v 1c4y 1d6w 1d9i
10230612 C.Dominguez, D.E.Duffy, Q.Han, R.S.Alexander, R.A.Galemmo, J.M.Park, P.C.Wong, E.C.Amparo, R.M.Knabb, J.Luettgen, and R.R.Wexler (1999).
Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors.
  Bioorg Med Chem Lett, 9, 925-930.  
10387040 H.Jhoti, A.Cleasby, S.Reid, P.J.Thomas, M.Weir, and A.Wonacott (1999).
Crystal structures of thrombin complexed to a novel series of synthetic inhibitors containing a 5,5-trans-lactone template.
  Biochemistry, 38, 7969-7977.
PDB codes: 1qhr 1qj1 1qj6 1qj7
  10422831 T.G.Davies, R.E.Hubbard, and J.R.Tame (1999).
Relating structure to thermodynamics: the crystal structures and binding affinity of eight OppA-peptide complexes.
  Protein Sci, 8, 1432-1444.
PDB codes: 1b0h 1b1h 1b2h 1b3h 1b4h 1b5h 1b6h 1b7h
  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.  
10089499 C.L.Strickland, J.M.Fevig, R.A.Galemmo, B.L.Wells, C.A.Kettner, and P.C.Weber (1998).
Biochemical and crystallographic characterization of homologous non-peptidic thrombin inhibitors having alternate binding modes.
  Acta Crystallogr D Biol Crystallogr, 54, 1207-1215.  
9772168 E.Skordalakes, S.Elgendy, C.A.Goodwin, D.Green, M.F.Scully, V.V.Kakkar, J.M.Freyssinet, G.Dodson, and J.J.Deadman (1998).
Bifunctional peptide boronate inhibitors of thrombin: crystallographic analysis of inhibition enhanced by linkage to an exosite 1 binding peptide.
  Biochemistry, 37, 14420-14427.
PDB codes: 1a3b 1a3e
9718968 H.Kubinyi (1998).
[Molecular similarity. 2. The structural basis of drug design]
  Pharm Unserer Zeit, 27, 158-172.  
9736918 J.A.Shafer (1998).
Cardiovascular chemotherapy: anticoagulants.
  Curr Opin Chem Biol, 2, 458-465.  
9724521 R.Krishnan, E.Zhang, K.Hakansson, R.K.Arni, A.Tulinsky, M.S.Lim-Wilby, O.E.Levy, J.E.Semple, and T.K.Brunck (1998).
Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes.
  Biochemistry, 37, 12094-12103.
PDB codes: 1ba8 1bb0 1ca8 1yyy 1zzz
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
  9792427 S.Tada, and J.J.Blow (1998).
The replication licensing system.
  Biol Chem, 379, 941-949.  
9083110 F.R.Salemme, J.Spurlino, and R.Bone (1997).
Serendipity meets precision: the integration of structure-based drug design and combinatorial chemistry for efficient drug discovery.
  Structure, 5, 319-324.  
9341205 S.L.Lee, R.S.Alexander, A.Smallwood, R.Trievel, L.Mersinger, P.C.Weber, and C.Kettner (1997).
New inhibitors of thrombin and other trypsin-like proteases: hydrogen bonding of an aromatic cyano group with a backbone amide of the P1 binding site replaces binding of a basic side chain.
  Biochemistry, 36, 13180-13186.
PDB code: 1auj
9334174 T.Mc Cormack, W.Baumeister, L.Grenier, C.Moomaw, L.Plamondon, B.Pramanik, C.Slaughter, F.Soucy, R.Stein, F.Zühl, and L.Dick (1997).
Active site-directed inhibitors of Rhodococcus 20 S proteasome. Kinetics and mechanism.
  J Biol Chem, 272, 26103-26109.  
9667850 W.C.Ripka (1997).
New thrombin inhibitors in cardiovascular disease.
  Curr Opin Chem Biol, 1, 242-253.  
8951649 A.Caflisch (1996).
Computational combinatorial ligand design: application to human alpha-thrombin.
  J Comput Aided Mol Des, 10, 372-396.  
  8762149 J.Féthière, Y.Tsuda, R.Coulombe, Y.Konishi, and M.Cygler (1996).
Crystal structure of two new bifunctional nonsubstrate type thrombin inhibitors complexed with human alpha-thrombin.
  Protein Sci, 5, 1174-1183.  
  8745399 M.F.Malley, L.Tabernero, C.Y.Chang, S.L.Ohringer, D.G.Roberts, J.Das, and J.S.Sack (1996).
Crystallographic determination of the structures of human alpha-thrombin complexed with BMS-186282 and BMS-189090.
  Protein Sci, 5, 221-228.
PDB codes: 1bmm 1bmn
8786410 P.D.Grootenhuis, and M.Karplus (1996).
Functionality map analysis of the active site cleft of human thrombin.
  J Comput Aided Mol Des, 10, 1.  
8703940 V.L.Nienaber, L.J.Mersinger, and C.A.Kettner (1996).
Structure-based understanding of ligand affinity using human thrombin as a model system.
  Biochemistry, 35, 9690-9699.  
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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