PDBsum entry 2zhr

Hydrolase/hydrolase inhibitor

PDB id: 2zhr

Contents

Protein chains

390 a.a. *

Ligands

GLU-VAL-ASN-1OL-ALA-GLU-PHE ×2

Waters ×622

* Residue conservation analysis

PDB id:

2zhr

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of bace1 in complex with om99-2 at ph 5.0

Structure:

Beta-secretase 1. Chain: a, b. Fragment: catalytic domain, unp residues 45-454. Synonym: beta-site app cleaving enzyme 1, beta-site amyloid precursor protein cleaving enzyme 1, membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, asp 2, asp2, bace1. Engineered: yes. Inhibitor om99-2. Chain: c, d.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bace1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Synthetic: yes

Resolution:

2.50Å R-factor: 0.185 R-free: 0.240

Authors:

H.Shimizu,N.Nukina

Key ref:

H.Shimizu et al. (2008). Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production. Mol Cell Biol, 28, 3663-3671. PubMed id: 18378702

Date:

08-Feb-08 Release date: 22-Apr-08

Protein chains

P56817  (BACE1_HUMAN) -  Beta-secretase 1 from Homo sapiens

Seq: 501 a.a.

Struc: 390 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.23.46 - memapsin 2.

Mol Cell Biol 28:3663-3671 (2008)

PubMed id: 18378702

Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production.

H.Shimizu, A.Tosaki, K.Kaneko, T.Hisano, T.Sakurai, N.Nukina.

ABSTRACT

BACE1 (beta-secretase) is a transmembrane aspartic protease that cleaves the beta-amyloid precursor protein and generates the amyloid beta peptide (Abeta). BACE1 cycles between the cell surface and the endosomal system many times and becomes activated interconvertibly during its cellular trafficking, leading to the production of Abeta. Here we report the crystal structure of the catalytically active form of BACE1. The active form has novel structural features involving the conformation of the flap and subsites that promote substrate binding. The functionally essential residues and water molecules are well defined and play a key role in the iterative activation of BACE1. We further describe the crystal structure of the dehydrated form of BACE1, showing that BACE1 activity is dependent on the dynamics of a catalytically required Asp-bound water molecule, which directly affects its catalytic properties. These findings provide insight into a novel regulation of BACE1 activity and elucidate how BACE1 modulates its activity during cellular trafficking.