General Information

The entry DI2010016 describes the same interaction with the disordered partner bearing different post-translational modification(s).

Database Accession: DI2010015

Name: Complex of human alpha-thrombin and unmodified recombinant hirudin

PDB ID: 4htc PDB

Experimental method: X-ray (2.30 Å)

Source organism: Hirudo medicinalis / Homo sapiens

Proof of disorder: Inferred from homology

Primary publication of the structure:

Rydel TJ, Tulinsky A, Bode W, Huber R
Refined structure of the hirudin-thrombin complex.

(1991) J. Mol. Biol. 221: 583-601

PMID: 1920434 PubMed

Abstract:

The structure of a recombinant hirudin (variant 2, Lys47) human alpha-thrombin complex has been refined using restrained least-squares methods to a crystallographic R-factor of 0.173. The hirudin structure consists of an N-terminal domain folded into a globular unit and a long 17-peptide C-terminal in an extended chain conformation. The N-terminal domain binds at the active-site of thrombin where Ile1' to Tyr3' penetrates to the catalytic triad. The alpha-amino group of Ile1' of hirudin makes a hydrogen bond with OG of Ser195 of thrombin, the side-chains of Ile1' and Tyr3' occupy the apolar site, Thr2' is at the entrance to, but does not enter, the S1 specificity site and Ile1' to Tyr3' form a parallel beta-strand with Ser214 to Gly219. The latter interaction is antiparallel in all other serine proteinase-protein inhibitor complexes. The extended C-terminal segment of hirudin, which is abundant in acidic residues, makes many electrostatic interactions with the fibrinogen binding exosite while the last five residues are in a 3(10) helical turn residing in a hydrophobic patch on the thrombin surface. The precision of the complementarity displayed by these two molecules produces numerous interactions, which although independently generally weak, together are responsible for the high degree of affinity and specificity. Although hirudin-thrombin and D-Phe-Pro-Arg-chloromethyl ketone-thrombin differ in conformation in the autolysis loop (Lys145 to Gly150), this is most likely due to different crystal packing interactions and changes in circular dichroism between the two are probably due to the inherent flexibility of the loop. An RGD sequence, which is generally known to be involved in cell surface receptor interactions, occurs in thrombin and is associated with a long solvent channel filled with water molecules leading to the surface from the end of the S1 site. However, the RGD triplet does not appear to be able to interact in concert in a surface binding mode.


Function and Biology Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown.

Molecular function: not assigned

Biological process:

negative regulation of proteolysis Any process that stops, prevents, or reduces the frequency, rate or extent of the hydrolysis of a peptide bond or bonds within a protein. GeneOntology

Cellular component:

extracellular region The space external to the outermost structure of a cell. For cells without external protective or external encapsulating structures this refers to space outside of the plasma membrane. This term covers the host cell environment outside an intracellular parasite. GeneOntology

Structure Summary Structural annotations of the participating protein chains.

Entry contents: 3 distinct polypeptide molecules

Chains: I, H, L

Notes: No modifications of the original PDB file.

Chain I

Name: Hirudin variant-2 (Fragment) Disordered Inferred from homology

Source organism: Hirudo medicinalis

Length: 65 residues

Sequence:Sequence according to PDB SEQRESITYTDCTESGQNLCLCEGSNVCGKGNKCILGSNGKGNQCVTGEGTPKPESHNNGDFEEIPEEYLQ

UniProtKB AC: P09945 (positions: 8-72) UniProt Coverage: 90.3%

UniRef90 AC: UniRef90_P09945 (positions: 8-72) UniRef90

Chain H

Name: Prothrombin Ordered component

Source organism: Homo sapiens

Length: 259 residues

Sequence:Sequence according to PDB SEQRESIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKLKKPVAFSDYIHPVCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVCKDSTRIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKYGFYTHVFRLKKWIQKVIDQFGE

UniProtKB AC: P00734 (positions: 364-622) UniProt Coverage: 41.6%

UniRef90 AC: UniRef90_P00734 (positions: 364-622) UniRef90

Chain L

Name: Prothrombin Ordered component

Source organism: Homo sapiens

Length: 36 residues

Sequence:Sequence according to PDB SEQRESTFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGR

UniProtKB AC: P00734 (positions: 328-363) UniProt Coverage: 5.8%

UniRef90 AC: UniRef90_P00734 (positions: 328-363) UniRef90

Evidence Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding.

Chain I: Disordered Inferred from homology

The interacting region of a closely homologous variant of hirudin has been shown to be intrinsically disordered (PMID: 1335515).

Chain H: Ordered component

Thrombin consists of a large and a small subunit. Trypsin domain of the large subunit involved in the interaction is known to adopt a stable structure in isolation (see Pfam domain PF00089). A solved structure of the thrombin dimer is represented by PDB ID 1jou.

Chain L: Ordered component

Thrombin consists of a large and a small subunit. Trypsin domain of the large subunit involved in the interaction is known to adopt a stable structure in isolation (see Pfam domain PF00089). A solved structure of the thrombin dimer is represented by PDB ID 1jou.

Related Structure(s) Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap).

There are 9 related structures in the Protein Data Bank:


The molecule viewer shows the original PDB stucture.

The structure can be rotated by left click and hold anywhere on the structure. Representation options can be edited by right clicking on the structure window.

Download the original structure (.pdb)

Download this entry's XML file (.xml)