2QZK

Crystal structure of human Beta Secretase complexed with I21

PDB DOI: https://doi.org/10.2210/pdb2QZK/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2007-08-16 Released: 2008-04-29
Deposition Author(s): Munshi, S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.227
R-Value Work: 0.206

wwPDB Validation 3D Report Full Report

This is version 1.3 of the entry. See complete history.

Literature

Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors.

Moore, K.P., Zhu, H., Rajapakse, H.A., McGaughey, G.B., Colussi, D., Price, E.A., Sankaranarayanan, S., Simon, A.J., Pudvah, N.T., Hochman, J.H., Allison, T., Munshi, S.K., Graham, S.L., Vacca, J.P., Nantermet, P.G.

(2007) Bioorg Med Chem Lett 17: 5831-5835

PubMed: 17827011 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2007.08.040
Primary Citation of Related Structures:
2PH8, 2QZK

PubMed Abstract:
This letter describes replacements for the P3 amide moiety present in previously reported tertiary carbinamine macrolactones. Although P-gp efflux issues associated with these amide-macrolactones were solved and full brain penetration was measured in one case, potency was compromised in the process.

Organizational Affiliation

Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. keith_moore2@merck.com

Macromolecule Content

Total Structure Weight: 45.65 kDa
Atom Count: 3,242
Modelled Residue Count: 376
Deposited Residue Count: 405
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Beta-secretase 1	A	405	Homo sapiens	Mutation(s): 2 Gene Names: BACE1, BACE 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 Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P56817
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
I21 Query on I21 Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	2-[(5R)-5-amino-5-methyl-4,16-dioxo-14-phenyl-3-oxa-15-azatricyclo[15.3.1.1~7,11~]docosa-1(21),7(22),8,10,12,14,17,19-octaen-19-yl]benzonitrile C₃₄ H₂₇ N₃ O₃ GWSQLGYWQZHSHS-UUWRZZSWSA-N		Interactions Focus chain B [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
I21	PDBBind: 2QZK	IC50: 27 (nM) from 1 assay(s)
I21	Binding MOAD: 2QZK	IC50: 27 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.227
R-Value Work: 0.206
Space Group: C 2 2 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 103.685	α = 90
b = 127.495	β = 90
c = 76.41	γ = 90

Software Package:

Software Name	Purpose
CNX	refinement
CrystalClear	data collection
HKL-2000	data reduction
HKL-2000	data scaling
CNX	phasing

Structure Validation

View Full Validation Report

Entry History

Deposition Data

Released Date: 2008-04-29

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2008-04-29
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2021-10-20
Changes: Database references, Derived calculations
Version 1.3: 2023-08-30
Changes: Data collection, Refinement description

RCSB PDB Core Operations are funded by the National Science Foundation (DBI-1832184), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM133198.