PDBsum entry: 1wss

Hydrolase/blood clotting

PDB-id: 1wss

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

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PROCHECK

Protein chains

142 a.a. *

254 a.a. *

191 a.a. *

Ligands

BGC

FUC

3CB

Metal ions

_CA ×9

Waters ×319

* Residue conservation analysis

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PDB id:

1wss

Name:

Hydrolase/blood clotting

Title:

Human factor viia-tissue factor in complex with peprid mimetic inhibitor that has two charge 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.

Biological unit:

Trimer (from PQS)

UniProt:

Chain L: P08709 (FA7_HUMAN)

Seq:
Struc:
	Seq:	466 a.a.
	Struc:	142 a.a.*

Chain H: P08709 (FA7_HUMAN)

Seq:
Struc:
	Seq:	466 a.a.
	Struc:	254 a.a.

Chain T: P13726 (TF_HUMAN)

Seq:

Struc:

Seq:

295 a.a.

Struc:

191 a.a.

Key:	PfamA domain
Secondary structure	CATH domain

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

Enzyme class:

Chains L, H: E.C.3.4.21.21   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

Hydrolyzes one Arg-|-Ile bond in factor X to form factor Xa.

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

Related entries:

1wqv
the same protein complexed with another inhibitor.
1dan
the same protein complexed with irreversible inhibitor.

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Key reference

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 the author.