PDBsum entry 6jsf

Hydrolase

PDB id: 6jsf

Contents

Protein chain

374 a.a.

Ligands

DMS ×2

C7X

Metals

IOD ×7

Waters ×154

PDB id:

6jsf

Name:

Hydrolase

Title:

Crystal structure of bace1 in complex with n-(3-((4s,5s)-2-amino-4- methyl-5-phenyl-5,6-dihydro-4h-1,3-thiazin-4-yl)-4-fluorophenyl)-5- (fluoromethoxy)pyrazine-2-carboxamide

Structure:

Beta-secretase 1. Chain: a. Synonym: aspartyl protease 2,asp 2,beta-site amyloid precursor protein cleaving enzyme 1,beta-site app cleaving enzyme 1,memapsin-2, membrane-associated aspartic protease 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bace1, bace, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.30Å R-factor: 0.186 R-free: 0.213

Authors:

K.Fujimoto,E.Matsuoka,N.Asada,G.Tadano,T.Yamamoto,K.Nakahara, K.Fuchino,H.Ito,N.Kanegawa,D.Moechars,H.J.M.Gijsen,K.I.Kusakabe

Key ref:

K.Fujimoto et al. (2019). Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2. J Med Chem, 62, 5080-5095. PubMed id: 31021626 DOI: 10.1021/acs.jmedchem.9b00309

Date:

08-Apr-19 Release date: 28-Aug-19

Protein chain

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

Seq: 501 a.a.

Struc: 374 a.a.

Enzyme reactions

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

DOI no: 10.1021/acs.jmedchem.9b00309

J Med Chem 62:5080-5095 (2019)

PubMed id: 31021626

Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2.

K.Fujimoto, E.Matsuoka, N.Asada, G.Tadano, T.Yamamoto, K.Nakahara, K.Fuchino, H.Ito, N.Kanegawa, D.Moechars, H.J.M.Gijsen, K.I.Kusakabe.

ABSTRACT

BACE1 inhibitors hold potential as agents in disease-modifying treatment for Alzheimer's disease. BACE2 cleaves the melanocyte protein PMEL in pigment cells of the skin and eye, generating melanin pigments. This role of BACE2 implies that nonselective and chronic inhibition of BACE1 may cause side effects derived from BACE2. Herein, we describe the discovery of potent and selective BACE1 inhibitors using structure-based drug design. We targeted the flap region, where the shape and flexibility differ between these enzymes. Analysis of the cocrystal structures of an initial lead 8 prompted us to incorporate spirocycles followed by its fine-tuning, culminating in highly selective compounds 21 and 22. The structures of 22 bound to BACE1 and BACE2 revealed that a relatively high energetic penalty in the flap of the 22-bound BACE2 structure may cause a loss in BACE2 potency, thereby leading to its high selectivity. These findings and insights should contribute to responding to the challenges in exploring selective BACE1 inhibitors.