5WAA

Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) C84R mutant


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.10 Å
  • R-Value Free: 0.149 
  • R-Value Work: 0.133 
  • R-Value Observed: 0.134 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia.

Shah, R.M.Maize, K.M.West, H.T.Strom, A.M.Finzel, B.C.Wagner, C.R.

(2018) J Mol Biol 430: 2709-2721

  • DOI: https://doi.org/10.1016/j.jmb.2018.05.028
  • Primary Citation of Related Structures:  
    5WAA

  • PubMed Abstract: 

    Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in human histidine nucleotide-binding protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations. Our findings indicate that half of the mutations (R37P, G93D and W123*) resulted in a destabilization of the dimeric state and a significant decrease in catalytic activity and HINT1 inhibitor binding affinity. The H112N mutant was found to be dimeric, but devoid of catalytic activity, due to the loss of the catalytically essential histidine; nevertheless, it exhibited high affinity to AMP and a HINT1 inhibitor. In contrast to the active-site mutants, the catalytic activity and dimeric structure of the surface mutants, C84R and G89V, were found to be similar to the wild-type enzyme. Taken together, our results suggest that the pathophysiology of inherited axonal neuropathy with neuromyotonia can be induced by conversion of HINT1 from a homodimer to monomer, by modification of select surface residues or by a significant reduction of the enzyme's catalytic efficiency.


  • Organizational Affiliation

    Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histidine triad nucleotide-binding protein 1
A, B
129Homo sapiensMutation(s): 1 
Gene Names: HINT1HINTPKCI1PRKCNH1
EC: 3
UniProt & NIH Common Fund Data Resources
Find proteins for P49773 (Homo sapiens)
Explore P49773 
Go to UniProtKB:  P49773
PHAROS:  P49773
GTEx:  ENSG00000169567 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49773
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth B]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.10 Å
  • R-Value Free: 0.149 
  • R-Value Work: 0.133 
  • R-Value Observed: 0.134 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.698α = 90
b = 46.323β = 94.18
c = 63.906γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data scaling
PDB_EXTRACTdata extraction
PHASERphasing
HKL-2000data reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-06
    Type: Initial release
  • Version 1.1: 2018-08-08
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Refinement description