PDBsum entry: 1zcm

Hydrolase

PDB-id: 1zcm

Contents

Description

Header details

Header records

References

PROCHECK

Protein chain

321 a.a. *

Ligands

C1N

Metal ions

_CA ×2

Waters ×206

* Residue conservation analysis

Tools

Clefts Calculation

PDB id:

1zcm

Name:

Hydrolase

Title:

Human calpain protease core inhibited by zllych2f

Structure:

Calpain 1, large [catalytic] subunit. Chain: a. Fragment: residues 33 to 353. Synonym: calcium-activated neutral proteinase, canp, mu- type, mucanp, micromolar-calpain. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: capn1, canpl1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

UniProt:

P07384 (CAN1_HUMAN)

Seq:

Struc:

Seq:

Struc:

Seq:

714 a.a.

Struc:

321 a.a.*

Key:

PfamA domain

Secondary structure

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme class:

E.C.3.4.22.52   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Cofactor:

Calcium

Resolution:

2.00Å

R-factor:

0.182

R-free:

0.223

Authors:

Q.Li,R.P.Hanzlik,R.F.Weaver,E.Schonbrunn

Key ref:

Q.Li et al. (2006). Molecular mode of action of a covalently inhibiting peptidomimetic on the human calpain protease core(,).. Biochemistry, 45, 701-708. [PubMed id: 16411745] [DOI: 10.1021/bi052077b]

Date:

12-Apr-05

Release date:

31-Jan-06

Quick_links

Procheck

Clefts

Surface

Key reference

DOI no: 10.1021/bi052077b

Biochemistry 45:701-708 (2006)

PubMed id: 16411745

Molecular mode of action of a covalently inhibiting peptidomimetic on the human calpain protease core(,).

Q.Li, R.P.Hanzlik, R.F.Weaver, E.Schönbrunn.

ABSTRACT

Calpain is a nearly ubiquitous Ca(2+)-activated proteolytic enzyme whose precise physiological function is unknown. However, aberrant Ca(2+) homeostasis in the course of cellular injuries and certain diseases of the CNS appears to activate calpain, in turn promoting the degradation of key cytoskeletal and membrane proteins. Hyperactive calpain has also been implicated in various aging phenomena and diseases of late life. Therefore, calpain is considered a potential therapeutic target in preventing degenerations of many kinds. Despite its potential medicinal importance, known structural information about mu-calpain is limited to that from the rat enzyme. We have determined the crystal structure of the human mu-calpain protease core (hmuI-II) containing a Gly213Ala mutation and covalently inactivated by a peptidomimetic (ZLLYCH(2)F) at 2.0 A resolution. The methylene carbon of the inhibitor is bound to Cys115. Additional hydrogen bonding and hydrophobic interactions between active site residues and the inhibitor, including an intermolecular antiparallel beta-sheet arrangement characteristically observed with members of the papain family of cysteine proteinases, help to stabilize the complex and orient the inhibitor. The terminal ZL portion of the inhibitor is solvent-exposed and highly flexible, and is thus not involved in specific binding interactions with the enzyme. Two large enzyme regions flanking the active site are highly flexible; they may be important in recognition of calpain's natural protein substrates and in positioning them for catalysis. The implications for drug design are discussed.