2P3W

Crystal Structure of the HtrA3 PDZ Domain Bound to a Phage-Derived Ligand (FGRWV)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.184 

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This is version 1.3 of the entry. See complete history


Literature

Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3.

Runyon, S.T.Zhang, Y.Appleton, B.A.Sazinsky, S.L.Wu, P.Pan, B.Wiesmann, C.Skelton, N.J.Sidhu, S.S.

(2007) Protein Sci 16: 2454-2471

  • DOI: https://doi.org/10.1110/ps.073049407
  • Primary Citation of Related Structures:  
    2JOA, 2P3W

  • PubMed Abstract: 

    High-temperature requirement A (HtrA) and its homologs contain a serine protease domain followed by one or two PDZ domains. Bacterial HtrA proteins and the mitochondrial protein HtrA2/Omi maintain cell function by acting as both molecular chaperones and proteases to manage misfolded proteins. The biological roles of the mammalian family members HtrA1 and HtrA3 are less clear. We report a detailed structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3 using peptide libraries and affinity assays to define specificity, structural studies to view the molecular details of ligand recognition, and alanine scanning mutagenesis to investigate the energetic contributions of individual residues to ligand binding. In common with HtrA2/Omi, we show that the PDZ domains of HtrA1 and HtrA3 recognize hydrophobic polypeptides, and while C-terminal sequences are preferred, internal sequences are also recognized. However, the details of the interactions differ, as different domains rely on interactions with different residues within the ligand to achieve high affinity binding. The results suggest that mammalian HtrA PDZ domains interact with a broad range of hydrophobic binding partners. This promiscuous specificity resembles that of bacterial HtrA family members and suggests a similar function for recognizing misfolded polypeptides with exposed hydrophobic sequences. Our results support a common activation mechanism for the HtrA family, whereby hydrophobic peptides bind to the PDZ domain and induce conformational changes that activate the protease. Such a mechanism is well suited to proteases evolved for the recognition and degradation of misfolded proteins.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Genetech, Inc., South San Francisco, CA 94080, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Probable serine protease HTRA3
A, B
112Homo sapiensMutation(s): 0 
Gene Names: HTRA3PRSP
EC: 3.4.21
UniProt & NIH Common Fund Data Resources
Find proteins for P83110 (Homo sapiens)
Explore P83110 
Go to UniProtKB:  P83110
PHAROS:  P83110
GTEx:  ENSG00000170801 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP83110
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.184 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.001α = 90
b = 73.001β = 90
c = 80.058γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-11-06
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2017-10-18
    Changes: Refinement description
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Refinement description