PDBsum entry 4phn

Hydrolase

PDB id: 4phn

Contents

Protein chains

173 a.a.

Metals

_CA ×8

Waters ×282

PDB id:

4phn

Name:

Hydrolase

Title:

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

Structure:

Calpain small subunit 1. Chain: a, b. Fragment: pef(s) domain vi, residues 94-266. Synonym: css1,calcium-activated neutral proteinase small subunit,canp small subunit,calcium-dependent protease small subunit,cdps,calcium- dependent protease small subunit 1,calpain regulatory subunit. Engineered: yes

Source:

Sus scrofa. Pig. Organism_taxid: 9823. Gene: capns1, capn4. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.79Å R-factor: 0.186 R-free: 0.228

Authors:

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

Key ref:

S.E.Adams et al. (2014). The structural basis of differential inhibition of human calpain by indole and phenyl α-mercaptoacrylic acids. J Struct Biol, 187, 236-241. PubMed id: 25086406 DOI: 10.1016/j.jsb.2014.07.004

Date:

06-May-14 Release date: 13-Aug-14

Protein chains

P04574  (CPNS1_PIG) -  Calpain small subunit 1 from Sus scrofa

Seq: 266 a.a.

Struc: 173 a.a.

DOI no: 10.1016/j.jsb.2014.07.004

J Struct Biol 187:236-241 (2014)

PubMed id: 25086406

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

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

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 2.03Å 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.