PDBsum entry 3kn0

Hydrolase

PDB id: 3kn0

Contents

Protein chains

387 a.a. *

Ligands

3TO ×2

TLA ×2

Waters ×942

* Residue conservation analysis

PDB id:

3kn0

Name:

Hydrolase

Title:

Structure of bace bound to sch708236

Structure:

Beta-secretase 1. Chain: a, b. Fragment: unp residues 55-447. Synonym: beta-site amyloid protein cleaving enzyme 1, beta-site ap cleaving enzyme 1, membrane-associated aspartic protease 2, memapsin- 2, aspartyl protease 2, asp 2, asp2. Engineered: yes

Source:

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

Resolution:

1.90Å R-factor: 0.188 R-free: 0.222

Authors:

C.Strickland,Y.Wang

Key ref:

Y.S.Wang et al. (2010). Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1) inhibitors. J Med Chem, 53, 942-950. PubMed id: 20043700

Date:

11-Nov-09 Release date: 19-Jan-10

Protein chains

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

Seq: 501 a.a.

Struc: 387 a.a.

Enzyme reactions

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

J Med Chem 53:942-950 (2010)

PubMed id: 20043700

Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1) inhibitors.

Y.S.Wang, C.Strickland, J.H.Voigt, M.E.Kennedy, B.M.Beyer, M.M.Senior, E.M.Smith, T.L.Nechuta, V.S.Madison, M.Czarniecki, B.A.McKittrick, A.W.Stamford, E.M.Parker, J.C.Hunter, W.J.Greenlee, D.F.Wyss.

ABSTRACT

Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper