6JSG

Crystal Structure of BACE1 in complex with N-{3-[(4S)-2-amino-4-methyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-chloropyridine-2-carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

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

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

(2019) J Med Chem 62: 5080-5095

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00309
  • Primary Citation of Related Structures:  
    6JSE, 6JSF, 6JSG, 6JSN, 6JSZ

  • PubMed 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.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1416Homo sapiensMutation(s): 0 
Gene Names: BACE1BACEKIAA1149
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
C6U
Query on C6U

Download Ideal Coordinates CCD File 
H [auth A]N-[3-[(4S)-2-azanyl-4-methyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-5-chloranyl-pyridine-2-carboxamide
C17 H16 Cl F N4 O S
VVZZZUNCWSTIOI-KRWDZBQOSA-N
IOD
Query on IOD

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A],
D [auth A]
IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
E [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
C6U BindingDB:  6JSG IC50: min: 0.84, max: 27 (nM) from 8 assay(s)
Binding MOAD:  6JSG IC50: 4.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 101.972α = 90
b = 101.972β = 90
c = 169.792γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
d*TREKdata reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2019-08-28
    Type: Initial release
  • Version 1.1: 2023-11-22
    Changes: Data collection, Database references, Refinement description