PDBsum entry 4isl

Hydrolase/hydrolase inhibitor

PDB id: 4isl

Contents

Protein chains

60 a.a.

241 a.a.

Ligands

PG4

GOL ×3

PGE

GSH

Waters ×172

PDB id:

4isl

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of the inactive matriptase in complex with its inhibitor hai-1

Structure:

Kunitz-type protease inhibitor 1. Chain: b. Fragment: kunitz domain i (unp residues 245-304). Synonym: hepatocyte growth factor activator inhibitor type 1, hai-1. Engineered: yes. Suppressor of tumorigenicity 14 protein. Chain: a. Fragment: serine protease domain (unp residues 615-855). Synonym: matriptase, membrane-type serine protease 1, mt-sp1,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hai1, spint1, unq223/pro256. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227. Gene: prss14, snc19, st14, tadg15. Expressed in: komagataella pastoris. Expression_system_taxid: 4922.

Resolution:

2.29Å R-factor: 0.186 R-free: 0.232

Authors:

M.D.Huang,B.Y.Zhao,C.Yuan,R.Li

Key ref:

B.Zhao et al. (2013). Crystal structures of matriptase in complex with its inhibitor hepatocyte growth factor activator inhibitor-1. J Biol Chem, 288, 11155-11164. PubMed id: 23443661 DOI: 10.1074/jbc.M113.454611

Date:

16-Jan-13 Release date: 06-Mar-13

Protein chain

O43278  (SPIT1_HUMAN) -  Kunitz-type protease inhibitor 1 from Homo sapiens

Seq: 529 a.a.

Struc: 60 a.a.

Protein chain

Q9Y5Y6  (ST14_HUMAN) -  Suppressor of tumorigenicity 14 protein from Homo sapiens

Seq: 855 a.a.

Struc: 241 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.3.4.21.109 - matriptase.

DOI no: 10.1074/jbc.M113.454611

J Biol Chem 288:11155-11164 (2013)

PubMed id: 23443661

Crystal structures of matriptase in complex with its inhibitor hepatocyte growth factor activator inhibitor-1.

B.Zhao, C.Yuan, R.Li, D.Qu, M.Huang, J.C.Ngo.

ABSTRACT

Matriptase, a type II trans-membrane serine protease of the S1 trypsin-like family, is expressed on the surface of nearly all normal human epithelium and found in biological fluid-like human milk. Matriptase overexpression has been implicated in tumor progression in certain epithelium-derived cancer cells. Matriptase is tightly regulated by its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1). It has been demonstrated that the Kunitz domain I (KD1) but not Kunitz domain II (KD2) of HAI-1 is responsible for the inhibitory activity of HAI-1 against matriptase. To investigate the molecular basis of inhibition of matriptase by HAI-1, we solved several crystal structures of matriptase serine protease domain in complex with the fragments of HAI-1. Based on these structures, we found that the binding of KD1 was different from previously predicted binding mode. The P3 arginine residue occupies the S3 specificity pocket of matriptase, but not the S4 pocket as in the cases of hepatocyte growth factor activator·HAI-1 KD1 and matriptase·sunflower trypsin inhibitor-1 complexes. The long 60-loop of matriptase makes direct contact with HAI-1 but remains flexible even in the complexes, and its apex does not bind with KD1 tightly. The interactions between this unique 60-loop and KD1 may provide an opportunity to increase the specificity and inhibitory activity of KD1 for matriptase. Furthermore, comparison between KD1 and a homology model of HAI-1 KD2 rationalizes the structural basis of why KD1 but not KD2 is responsible for the inhibitory activity of HAI-1 against matriptase.