4PHM

The Structural Basis of Differential Inhibition of Human Calpain by Indole and Phenyl alpha-Mercaptoacrylic Acids


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 

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Ligand Structure Quality Assessment 


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Literature

The structural basis of differential inhibition of human calpain by indole and phenyl alpha-mercaptoacrylic acids.

Adams, S.E.Rizkallah, P.J.Miller, D.J.Robinson, E.J.Hallett, M.B.Allemann, R.K.

(2014) J Struct Biol 187: 236-241

  • DOI: https://doi.org/10.1016/j.jsb.2014.07.004
  • Primary Citation of Related Structures:  
    4PHJ, 4PHK, 4PHM, 4PHN

  • PubMed Abstract: 

    Excessive activity of neutrophils has been linked to many pathological conditions, including rheumatoid arthritis, cancer and Alzheimer's disease. Calpain-I is a Ca(2+)-dependent protease that plays a key role in the extravasation of neutrophils from the blood stream prior to causing damage within affected tissues. Inhibition of calpain-I with small molecule mercaptoacrylic acid derivatives slows the cell spreading process of live neutrophils and so these compounds represent promising drug leads. Here we present the 2.05 and 2.03 Å co-crystal X-ray structures of the pentaEF hand region, PEF(S), from human calpain with (Z)-3-(4-chlorophenyl)-2-mercaptoacrylic acid and (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid. In both structures, the α-mercaptoacrylic acid derivatives bind between two α-helices in a hydrophobic pocket that is also exploited by a leucine residue of the endogenous regulatory calpain inhibitor calpastatin. Hydrophobic interactions between the aromatic rings of both inhibitors and the aliphatic residues of the pocket are integral for tight binding. In the case of (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid, hydrogen bonds form between the mercaptoacrylic acid substituent lying outside the pocket and the protein and the carboxylate group is coplanar with the aromatic ring system. Multiple conformations of (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid were found within the pocket. The increased potency of (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid relative to (Z)-3-(4-chlorophenyl)-2-mercaptoacrylic acid may be a consequence of the indole group binding more deeply in the hydrophobic pocket of PEF(S) than the phenyl ring.


  • Organizational Affiliation

    School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff CF10 3AT, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Calpain small subunit 1
A, B
173Homo sapiensMutation(s): 0 
Gene Names: CAPNS1CAPN4CAPNS
UniProt & NIH Common Fund Data Resources
Find proteins for P04632 (Homo sapiens)
Explore P04632 
Go to UniProtKB:  P04632
PHAROS:  P04632
GTEx:  ENSG00000126247 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04632
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2UD
Query on 2UD

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
3-(5-bromo-1H-indol-3-yl)-2-thioxopropanoic acid
C11 H8 Br N O2 S
XFDKQHURWNNDLG-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
I [auth B]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
I [auth B],
J [auth B],
K [auth B],
L [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.41α = 90
b = 79.34β = 91.23
c = 57.26γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Medical Research Council (United Kingdom)United KingdomG0701192

Revision History  (Full details and data files)

  • Version 1.0: 2014-08-13
    Type: Initial release
  • Version 1.1: 2014-09-10
    Changes: Database references
  • Version 1.2: 2015-02-04
    Changes: Other
  • Version 2.0: 2017-09-13
    Changes: Advisory, Atomic model, Author supporting evidence, Derived calculations
  • Version 2.1: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Refinement description