PDBsum entry 1jmj

Blood clotting

PDB id: 1jmj

Contents

Protein chains

397 a.a. *

Ligands

NAG-NAG-BMA

NAG

Metals

_CA

Waters ×297

* Residue conservation analysis

PDB id:

1jmj

Name:

Blood clotting

Title:

Crystal structure of native heparin cofactor ii

Structure:

Heparin cofactor ii. Chain: a, b. Synonym: hc-ii. Protease inhibitor leuserpin 2. Hls2. Serine (or cysteine) proteinase inhibitor, clade d (heparin cofactor), member 1

Source:

Homo sapiens. Human. Organism_taxid: 9606

Biol. unit:

Dimer (from PQS)

Resolution:

2.35Å R-factor: 0.208 R-free: 0.255

Authors:

T.P.Baglin,R.W.Carrell,F.C.Church,J.A.Huntington

Key ref:

T.P.Baglin et al. (2002). Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism. Proc Natl Acad Sci U S A, 99, 11079-11084. PubMed id: 12169660 DOI: 10.1073/pnas.162232399

Date:

18-Jul-01 Release date: 30-Aug-02

Protein chains

P05546  (HEP2_HUMAN) -  Heparin cofactor 2 from Homo sapiens

Seq: 499 a.a.

Struc: 397 a.a.

DOI no: 10.1073/pnas.162232399

Proc Natl Acad Sci U S A 99:11079-11084 (2002)

PubMed id: 12169660

Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism.

T.P.Baglin, R.W.Carrell, F.C.Church, C.T.Esmon, J.A.Huntington.

ABSTRACT

The serine proteases sequentially activated to form a fibrin clot are inhibited primarily by members of the serpin family, which use a unique beta-sheet expansion mechanism to trap and destroy their targets. Since the discovery that serpins were a family of serine protease inhibitors there has been controversy as to the role of conformational change in their mechanism. It now is clear that protease inhibition depends entirely on rapid serpin beta-sheet expansion after proteolytic attack. The regulatory advantage afforded by the conformational mobility of serpins is demonstrated here by the structures of native and S195A thrombin-complexed heparin cofactor II (HCII). HCII inhibits thrombin, the final protease of the coagulation cascade, in a glycosaminoglycan-dependent manner that involves the release of a sequestered hirudin-like N-terminal tail for interaction with thrombin. The native structure of HCII resembles that of native antithrombin and suggests an alternative mechanism of allosteric activation, whereas the structure of the S195A thrombin-HCII complex defines the molecular basis of allostery. Together, these structures reveal a multistep allosteric mechanism that relies on sequential contraction and expansion of the central beta-sheet of HCII.

Selected figure(s)

Figure 2.
Fig 2. Crystallographic structure of the HCII-thrombin Michaelis complex. (a) A stereo representation of the Michaelis complex between S195A thrombin (cyan) and HCII (colored as described for Fig. 1), with the -loop in front and the 60-insertion loop behind the reactive center loop. (b) Stereo representation of the electron density covering the portion of the acidic tail (yellow) that interacts with thrombin (magenta), contoured at 1 . (c) The subsite interactions between the reactive center residues of HCII (rods) and the active site cleft of thrombin (surface representation) are extensive and complementary in both electrostatic (Left, negative potential is red, and positive is blue) and hydrophobic (Right, green for hydrophobic side chains) properties. (d) The interaction between exosite I of thrombin (surface representation as described for c) and the hirudin-like N-terminal tail of HCII (rods, the side chains of residues not interacting with thrombin were removed for clarity) is primarily hydrophobic. The only ionic interactions are between Asp-70 and Asp-72 of HCII and L110H of thrombin. Sulfated tyrosines, 60 and 73, make no contacts with thrombin and are not shown.

Figure 3.
Fig 3. The sequential mechanism of GAG-mediated thrombin inhibition by HCII (as described in Results and Discussion). For a video of this mechanism, see Movie 2.

Figures were selected by the author.