PDBsum entry: 1a3e

Complex (serine protease/inhibitor)

PDB-id

1a3e


	Biological unit* = asymmetric unit, as shown (as deduced by PQS*)

Contents

Description

Header details

Protein chains

Ligands

T16

Waters ×206

* Residue conservation analysis

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PDB id:

1a3e

Name:

Complex (serine protease/inhibitor)

Title:

Complex of human alpha-thrombin with the bifunctional boronate inhibitor borolog2

Structure:

Alpha-thrombin (small subunit). Chain: l. Alpha-thrombin (large subunit). Chain: h. Boronate inhibitor borolog2. Chain: i

Source:

Homo sapiens. Human. Organism_taxid: 9606. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421

Biological unit:

Trimer (from PQS)

UniProt:

Chain L: P00734 (THRB_HUMAN)

Seq:

Struc:


Seq:

Struc:


Seq:				622 a.a.

Struc:				27 a.a.

Chain H: P00734 (THRB_HUMAN)

Seq:

Struc:

Seq:

Struc:

Seq:

622 a.a.

Struc:

251 a.a.

Key:		PfamA domain
		Secondary structure			CATH domain

Enzyme class:

Chains L, H: E.C.3.4.21.5 [IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

Resolution:

1.85Å

R-factor:

0.170

R-free:

0.220

Authors:

E.Skordalakes,S.Elgendy,C.A.Goodwin,D.Green,M.F.Scullly, V.V.Kakkar,J.M.Freyssinet,G.Dodson,J.Deadman

Key ref:

A.Zdanov et al. (1993). Crystal structure of the complex of human alpha-thrombin and nonhydrolyzable bifunctional inhibitors, hirutonin-2 and hirutonin-6.. Proteins, 17, 252-265. [PubMed id: 8272424] [DOI: 10.1002/prot.340170304]

Date:

21-Jan-98

Release date:

03-Jun-98

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Key reference

DOI no: 10.1002/prot.340170304 Proteins 17:252-265 (1993)

PubMed id: 8272424

Crystal structure of the complex of human alpha-thrombin and nonhydrolyzable bifunctional inhibitors, hirutonin-2 and hirutonin-6.

A.Zdanov, S.Wu, J.DiMaio, Y.Konishi, Y.Li, X.Wu, B.F.Edwards, P.D.Martin, M.Cygler.

ABSTRACT

The crystal structure of the complexes of hirutonin-2 and hirutonin-6 with human alpha-thrombin have been solved and refined to R-factors of 0.169 (2.0 A resolution) and 0.162 (2.1 A), respectively. Hirutonins belong to a family of bifunctional inhibitors bearing a noncleavable moiety mimicking the scissile bond. Hirutonin-2 is an analog of (D)Phe-Pro-Arg-Gly-hirudin49-65; hirutonin-6 has the same N-terminal tripeptide connected to a shortened fibrinogen exosite-binding part by a short, nonpeptidyl linker. The hirutonin-6 molecule is well defined in the electron density with the exception of the C-terminal Leu-h61. The linker follows near the bottom of the canyon connecting the active site with the exosite, forms a short antiparallel beta-sheet-like arrangement with Leu40-Leu41 and makes van der Waals contacts with Glu39-Leu40-Leu41 of thrombin. In the thrombin-hirutonin-2 complex, the N- and C-terminal parts of the inhibitor are well ordered (except the C-terminal Gln-h65) while the central portion of the linker is partially disordered. The glycine analog in the P1' position of hirutonin-2 assumes a conformation similar to that of the canonical form (Bode and Huber (1992) Eur. J. Biochem. 204:433-451) and supports the identification of the S1' site as restricted by His57, Trp60D, Lys60F, and the Cys42-Cys58 disulfide bridge. The carbonyl oxygen of the P1 arginine residue is located in the oxyanion hole formed by the NH groups of Gly193 and Ser195, while the carbonyl carbon is positioned within a short distance, 2.8 A, from the O gamma of Ser195. This resembles the conformation of the substrate-like inhibitors bound to other serine proteases. The N-terminal (D)Phe-Pro-Arg fragment common to both inhibitors binds to thrombin in a fashion very similar to that of other inhibitors having this motif. The binding of the C-terminus of hirutonins to the fibrinogen-binding exosite is similar to that observed in hirudin and hirulog complexes.

Literature references that cite this PDB file's key reference

PubMed id Reference

16387853 A.Fernández, R.Scott, and R.S.Berry (2006).
Packing defects as selectivity switches for drug-based protein inhibitors.

Proc Natl Acad Sci U S A, 103, 323-328.

16338411 A.Fernández (2005).
Incomplete protein packing as a selectivity filter in drug design.

Structure, 13, 1829-1836.

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.

10694407 J.J.Slon-Usakiewicz, J.Sivaraman, Y.Li, M.Cygler, and Y.Konishi (2000).
Design of P1' and P3' residues of trivalent thrombin inhibitors and their crystal structures.

Biochemistry, 39, 2384-2391.

PDB codes: 1eoj 1eol

10336381 M.C.Maurer, J.Y.Trosset, C.C.Lester, E.E.DiBella, and H.A.Scheraga (1999).
New general approach for determining the solution structure of a ligand bound weakly to a receptor: structure of a fibrinogen Aalpha-like peptide bound to thrombin (S195A) obtained using NOE distance constraints and an ECEPP/3 flexible docking program.

Proteins, 34, 29-48.

9521099 G.De Simone, A.Lombardi, S.Galdiero, F.Nastri, R.Della Morte, N.Staiano, C.Pedone, M.Bolognesi, and V.Pavone (1998).
Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex.

Protein Sci, 7, 243-253.

PDB code: 5gds

9354617 J.J.Slon-Usakiewicz, E.Purisima, Y.Tsuda, T.Sulea, A.Pedyczak, J.Féthière, M.Cygler, and Y.Konishi (1997).
Nonpolar interactions of thrombin S' subsites with its bivalent inhibitor: methyl scan of the inhibitor linker.

Biochemistry, 36, 13494-13502.

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.

8913620 J.H.Matthews, R.Krishnan, M.J.Costanzo, B.E.Maryanoff, and A.Tulinsky (1996).
Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site.

Biophys J, 71, 2830-2839.

PDB codes: 1a4w 1tbz

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.

8855938 P.D.Martin, M.G.Malkowski, J.DiMaio, Y.Konishi, F.Ni, and B.F.Edwards (1996).
Bovine thrombin complexed with an uncleavable analog of residues 7-19 of fibrinogen A alpha: geometry of the catalytic triad and interactions of the P1', P2', and P3' substrate residues.

Biochemistry, 35, 13030-13039.

PDB code: 1ucy

8868478 R.Krishnan, A.Tulinsky, G.P.Vlasuk, D.Pearson, P.Vallar, P.Bergum, T.K.Brunck, and W.C.Ripka (1996).
Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic.

Protein Sci, 5, 422-433.

PDB code: 1dit

8732754 V.Ganesh, A.Y.Lee, J.Clardy, and A.Tulinsky (1996).
Comparison of the structures of the cyclotheonamide A complexes of human alpha-thrombin and bovine beta-trypsin.

Protein Sci, 5, 825-835.

8710824 S.Mosimann, R.Meleshko, and M.N.James (1995).
A critical assessment of comparative molecular modeling of tertiary structures of proteins.

Proteins, 23, 301-317.

7756983 J.Vijayalakshmi, K.P.Padmanabhan, K.G.Mann, and A.Tulinsky (1994).
The isomorphous structures of prethrombin2, hirugen-, and PPACK-thrombin: changes accompanying activation and exosite binding to thrombin.

Protein Sci, 3, 2254-2271.

PDB codes: 1hag 1hah 1hai

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.