RCSB PDB - 4ISN: Crystal Structure of Matriptase in complex with its inhibitor HAI-1

 4ISN

Crystal Structure of Matriptase in complex with its inhibitor HAI-1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.212 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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Literature

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

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

(2013) J Biol Chem 288: 11155-11164

  • DOI: https://doi.org/10.1074/jbc.M113.454611
  • Primary Citation of Related Structures:  
    4IS5, 4ISL, 4ISN, 4ISO

  • PubMed 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.


  • Organizational Affiliation

    State Key Lab of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Kunitz-type protease inhibitor 1A [auth B]62Homo sapiensMutation(s): 0 
Gene Names: SPINT1
UniProt & NIH Common Fund Data Resources
Find proteins for O43278 (Homo sapiens)
Explore O43278 
Go to UniProtKB:  O43278
PHAROS:  O43278
GTEx:  ENSG00000166145 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO43278
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Suppressor of tumorigenicity 14 proteinB [auth A]241Homo sapiensMutation(s): 1 
Gene Names: PRSS14SNC19ST14TADG15
EC: 3.4.21.109
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y5Y6 (Homo sapiens)
Explore Q9Y5Y6 
Go to UniProtKB:  Q9Y5Y6
PHAROS:  Q9Y5Y6
GTEx:  ENSG00000149418 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y5Y6
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.212 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.529α = 90
b = 64.529β = 90
c = 172.386γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted GSHClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-03-06
    Type: Initial release
  • Version 1.1: 2013-05-15
    Changes: Database references
  • Version 1.2: 2014-07-30
    Changes: Other
  • Version 1.3: 2017-11-15
    Changes: Refinement description
  • Version 1.4: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description