PDBsum entry 2asu

Hydrolase

PDB id: 2asu

Contents

Protein chain

225 a.a. *

Ligands

CYS-GLY-LYS-ARG

Waters ×155

* Residue conservation analysis

PDB id:

2asu

Name:

Hydrolase

Title:

Crystal structure of the beta-chain of hgfl/msp

Structure:

Hepatocyte growth factor-like protein. Chain: a. Fragment: alpha-chain. Synonym: macrophage stimulatory protein, msp, macrophage stimulating protein. Engineered: yes. Hepatocyte growth factor-like protein. Chain: b. Fragment: beta-chain.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mst1, hgfl. Expressed in: mus musculus. Expression_system_taxid: 10090.

Biol. unit:

Dimer (from PQS)

Resolution:

1.85Å R-factor: 0.200 R-free: 0.237

Authors:

F.Carafoli,D.Y.Chirgadze,T.L.Blundell,E.Gherardi

Key ref:

F.Carafoli et al. (2005). Crystal structure of the beta-chain of human hepatocyte growth factor-like/macrophage stimulating protein. FEBS J, 272, 5799-5807. PubMed id: 16279944 DOI: 10.1111/j.1742-4658.2005.04968.x

Date:

24-Aug-05 Release date: 10-Nov-05

Protein chain

P26927  (HGFL_HUMAN) -  Hepatocyte growth factor-like protein from Homo sapiens

Seq: 711 a.a.

Struc: 225 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1111/j.1742-4658.2005.04968.x

FEBS J 272:5799-5807 (2005)

PubMed id: 16279944

Crystal structure of the beta-chain of human hepatocyte growth factor-like/macrophage stimulating protein.

F.Carafoli, D.Y.Chirgadze, T.L.Blundell, E.Gherardi.

ABSTRACT

Hepatocyte growth factor like/macrophage stimulating protein (HGFl/MSP) and hepatocyte growth factor/scatter factor (HGF/SF) define a distinct family of vertebrate-specific growth factors structurally related to the blood proteinase precursor plasminogen and with important roles in development and cancer. Although the two proteins share a similar domain structure and mechanism of activation, there are differences between HGFl/MSP and HGF/SF in terms of the contribution of individual domains to receptor binding. Here we present a crystal structure of the 30 kDa beta-chain of human HGFl/MSP, a serine proteinase homology domain containing the high-affinity binding site for the RON receptor. The structure describes at 1.85 Angstrom resolution the region of the domain corresponding to the receptor binding site recently defined in the HGF/SF beta-chain, namely the central cleft harboring the three residues corresponding to the catalytic ones of active proteinases (numbers in brackets define the sequence position according to the standard chymotrypsinogen numbering system) and an adjacent loop flanking the S1 specificity pocket and containing residues Asn682 (c217) and Arg683 (c218) previously shown to be essential for binding of HGFl/MSP to the RON receptor. The study confirms the concept that the serine proteinase homology domains of HGFl/MSP and HGF/SF bind their receptors in an 'enzyme-substrate' mode, reflecting the common evolutionary origin of the plasminogen-related growth factors and the proteinases of the clotting and fibrinolytic pathways. However, analysis of the intermolecular interactions in the crystal lattice of beta-chain HGFl/MSP fails to show the same contacts seen in the HGF/SF structures and does not support a conserved mode of dimerization of the serine proteinase homology domains of HGFl/MSP and HGF/SF responsible for receptor activation.

Selected figure(s)

Figure 1.
Fig. 1. (A) Ribbon diagram of the -chain of HGFl/MSP. The three residues replacing the catalytic triad of active proteinases: Q522 (c57), Q568 (c102) and Y661 (c195) are shown as solid sticks. Also shown are the five intradomain disulfide bonds while a sixth disulfide connecting the - and -chains [Cys468-Cys588 (c122)] is not shown in the figure. L4, L5, L8, 10, L11 and L13 define loops discussed in the text and detailed in Fig. 2A. (B) Detailed view of the active site region of the -chain of HGFl/MSP. The three residues corresponding to the catalytic ones of actives serine proteinases are shown in red; residues corresponding to the S1 specificity pocket (L11) are shown in blue; a segment of the L13 loop is shown in yellow. The disulfide bond between C657 and C685 (c191-c220) is also shown. The figure was generated with PYMOL[36] and SPOCK (http://quorum.tamu.edu/Manual/).

Figure 3.
Fig. 3. (A) Structural alignment of a model of the single-chain, precursor form of the serine proteinase homology domain of HGFl/MSP (green) and the crystal structure of the corresponding two-chain form (pink). The model of the single chain form of the protein was constructed with MODELLER[39], using the atomic coordinates of the plasminogen -chain (pdb: 1QRZ) [24] as template. Residues discussed in the text are labeled and shown as solid sticks. The figure was generated with PYMOL [36]. (B) and (C) Surface representation of the serine proteinase domains of two-chain HGFl/MSP (b) and the model of single-chain HGFl/MSP (c). The amino acids shown in colour are either those corresponding to the catalytic triad (on the left) or amino acids in L13 that have been shown by mutagenesis to be involved in receptor binding. The figure has been prepared with SPOCK (http://quorum.tamu.edu/Manual/).

The above figures are reprinted by permission from the Federation of European Biochemical Societies: FEBS J (2005, 272, 5799-5807) copyright 2005.

Figures were selected by an automated process.