PDBsum entry 1wss

Hydrolase/blood clotting

PDB id: 1wss

Contents

Protein chains

142 a.a. *

254 a.a. *

191 a.a. *

Ligands

BGC

FUC

3CB

Metals

_CA ×9

Waters ×319

* Residue conservation analysis

PDB id:

1wss

Name:

Hydrolase/blood clotting

Title:

Human factor viia-tissue factor in complex with peptide-mimetic inhibitor that has two charged groups in p2 and p4

Structure:

Coagulation factor vii. Chain: l. Fragment: factor vii light chain. Synonym: serum prothrombin conversion accelerator, spca, proconvertin, eptacog alfa. Engineered: yes. Coagulation factor vii. Chain: h. Fragment: factor vii heavy chain.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell: cho. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Trimer (from PQS)

Resolution:

2.60Å R-factor: 0.218 R-free: 0.282

Authors:

S.Kadono,A.Sakamoto,Y.Kikuchi,M.Oh-Eda,N.Yabuta,T.Koga,K.Hattori, T.Shiraishi,M.Haramura,H.Kodama,Y.Ono,T.Esaki,H.Sato,Y.Watanabe, S.Itoh,M.Ohta,T.Kozono

Key ref:

S.Kadono et al. (2005). Structure of human factor VIIa/tissue factor in complex with a peptide-mimetic inhibitor: high selectivity against thrombin by introducing two charged groups in P2 and P4. Acta Crystallograph Sect F Struct Biol Cryst Commun, 61, 169-173. PubMed id: 16510984 DOI: 10.1107/S1744309105000047

Date:

10-Nov-04 Release date: 10-Nov-05

Protein chain

P08709  (FA7_HUMAN) -  Coagulation factor VII from Homo sapiens

Seq: 466 a.a.

Struc: 142 a.a.*

Protein chain

P08709  (FA7_HUMAN) -  Coagulation factor VII from Homo sapiens

Seq: 466 a.a.

Struc: 254 a.a.

Protein chain

P13726  (TF_HUMAN) -  Tissue factor from Homo sapiens

Seq: 295 a.a.

Struc: 191 a.a.

* PDB and UniProt seqs differ at 10 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains L, H: E.C.3.4.21.21 - coagulation factor VIIa.
• Reaction: Hydrolyzes one Arg-|-Ile bond in factor X to form factor Xa.

DOI no: 10.1107/S1744309105000047

Acta Crystallograph Sect F Struct Biol Cryst Commun 61:169-173 (2005)

PubMed id: 16510984

Structure of human factor VIIa/tissue factor in complex with a peptide-mimetic inhibitor: high selectivity against thrombin by introducing two charged groups in P2 and P4.

S.Kadono, A.Sakamoto, Y.Kikuchi, M.Oh-Eda, N.Yabuta, T.Koga, K.Hattori, T.Shiraishi, M.Haramura, H.Kodama, Y.Ono, T.Esaki, H.Sato, Y.Watanabe, S.Itoh, M.Ohta, T.Kozono.

ABSTRACT

The crystal structure of human factor VIIa/soluble tissue factor (FVIIa/sTF) in complex with a highly selective peptide-mimetic FVIIa inhibitor which shows 1670-fold selectivity against thrombin inhibition has been solved at 2.6 A resolution. The inhibitor is bound to FVIIa/sTF at the S1, S2 and S3 sites and at the additional S1 subsite. Two charged groups, the amidino group in P2 and the carboxylate group in P4, form ionic interactions with Asp60 and Lys192 of FVIIa, respectively. Structural comparisons between factor VIIa and thrombin show that thrombin has oppositely charged residues, Lys60F and Glu192, in the S2 site and the S1 subsites, respectively. These data suggest that the utilization of the differences of charge distribution in the S2 site and the S1 subsites between FVIIa and thrombin is critical for achieving high selectivity against thrombin inhibition. These results will provide valuable information for the structure-based drug design of specific inhibitors for FVIIa/TF.

Selected figure(s)

Figure 1.
Figure 1 Chemical structures of peptide-mimetic thrombin and factor VIIa inhibitors. Values in parentheses refer to the ratio against FVIIa/TF IC[50].

Figure 4.
Figure 4 X-ray crystal structure of compound (2) bound to factor VIIa/sTF. C atoms of compound (2) are shown in green.

The above figures are reprinted from an Open Access publication published by the IUCr: Acta Crystallograph Sect F Struct Biol Cryst Commun (2005, 61, 169-173) copyright 2005.

Figures were selected by an automated process.