1YM2: Crystal Structure Of Human Beta Secretase Complexed With Nvp-Aur200

Citation:
Abstract
Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent truncated analogue 5 with good selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane, cyclopentanone, tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with considerable variation at the P and P' sites. The cyclopentanone and 2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray cocrystal structures of two analogues 5 and 45 revealed excellent convergence with the original inhibitor 1 structure while providing new insights into other interactions which could be exploited for future modifications.
PDB ID: 1YM2Download
MMDB ID: 105344
PDB Deposition Date: 2005/1/20
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.05  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 1YM2: dimeric; determined by author and by software (PISA)
Molecular Components in 1YM2
Label Count Molecule
Proteins (2 molecules)
1
Beta-secretase 1(Gene symbol: BACE1)
Molecule annotation
1
Nvp-aur200 Inhibitor
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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