Crystal Structure of Human BACE2 in Complex with a Hydroxyethylamine Transition-state Inhibitor

Ostermann, Nils; Eder, Jörg; Eidhoff, Ulf; Zink, F.; Hassiepen, Ulrich; Worpenberg, Susanne; Maibaum, Jürgen; Simić, Oliver; Hommel, Ulrich; Gerhartz, Bernd

doi:10.1016/j.jmb.2005.10.027

Cited by 53 publications

(67 citation statements)

References 37 publications

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“…The BACE2 is a protein homologous to BACE1 24 ; however, we did not detect any BACE2 immunoreactivity in CSF by Western blot (data not shown), consistent with the previous study 25 that very low expression of BACE2 in the brain is nondetectable. In addition, although BACE1 and BACE2 are highly homologous, as demonstrated in recent studies on BACE2 structure, the structure of BACE2 revealed differences in the S3, S2, S1', and S2' active site substrate pockets compared with BACE1, 26 indicating that BACE1 and BACE2 show different substrate specificity. Also, Sun et al 27 found that an increase in BACE2 expression did not entail an increase in C99 production, such as that produced by BACE1.…”

Section: Commentmentioning

confidence: 73%

Levels of β-Secretase (BACE1) in Cerebrospinal Fluid as a Predictor of Risk in Mild Cognitive Impairment

Zhong

Ewers

Teipel

et al. 2007

Arch Gen Psychiatry

195

140

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Context: Elevated ␤-secretase (␤-site amyloid precursor protein-cleaving enzyme 1 [BACE1]) activity has been found in the brains of patients with sporadic Alzheimer disease (AD) compared with controls. Now we are particularly interested in whether BACE1 can be identified in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI), a population at high risk for AD. The possible presence of BACE1 in the CSF of patients with AD and MCI has so far gone unreported.Objective: To examine whether BACE1 can be identified in the CSF of patients with MCI.Design: We evaluated CSF BACE1 levels using 2 sandwich enzyme-linked immunosorbent assays, BACE1 enzymatic activities by means of synthetic fluorescence substrate, and total amyloid-␤ peptide levels using a sandwich enzyme-linked immunosorbent assay.Setting: Two independent research centers.Participants: Eighty patients with sporadic AD, 59 patients with MCI, and 69 controls.Main Outcome Measures: BACE1 levels and enzymatic activities and amyloid-␤ peptide levels. Conclusion: Significant elevation of BACE1 levels and activity in CSF is an indicator of MCI, which could be an early stage of AD. Psychiatry. 2007;64:718-726 A LZHEIMER DISEASE (AD) IS characterized by the progressive formation of insoluble amyloid plaques and vascular deposits consisting of the 4-kDa amyloid-␤ peptide (A␤) in the brain. Arch Gen1 ␤-Secretase (␤-site amyloid precursor protein-cleaving en-2 is one of the 2 key enzymes in amyloid precursor protein (APP) processing. Amyloid-␤ peptide results from cleavage of APP initially by BACE1 to produce a C99 fragment and release soluble APP␤; C99 is then further cleaved by ␥-secretase, leading to A␤. Increased BACE1 activity and elevated levels of insoluble A␤ have been shown in the brains of patients with sporadic AD. 3,4 Because cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the central nervous system, biochemical changes in the brain could potentially be reflected in CSF. The CSF-based detection of BACE1 levels and activity might be valuable in aiding the early diagnosis of AD, especially in patients with mild cognitive impairment (MCI), who show a higher risk of AD.5 Several recent studies [6][7][8] showed that BACE1 activity can be detected in the CSF. However, whether changes could occur in BACE1 activity or protein levels in the CSF of patients with AD or MCI remains unknown.In the present study, we quantitatively analyzed the enzymatic activities and protein levels of BACE1 and total A␤ levels in CSF samples from 208 individuals. We aim to determine whether BACE1 levels and activity can be detected in CSF, whether they are altered in AD compared with healthy aging, and whether levels of BACE1 protein and activity may be useful to discriminate patients with AD or MCI from healthy individuals.

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Section: Commentmentioning

confidence: 73%

Levels of β-Secretase (BACE1) in Cerebrospinal Fluid as a Predictor of Risk in Mild Cognitive Impairment

Zhong

Ewers

Teipel

et al. 2007

Arch Gen Psychiatry

195

140

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“…tertiary structure would be similar to BACE-1 but with the predicted absence of 1 disulfide bond. Again, this was disproved with a subsequent X-ray structure [Ostermann et al, 2006], which demonstrated that the discrepancy stemmed from a misalignment of the C-terminal domains of BACE-1 and BACE-2. This serves as a cautionary tale, that even when creating homology models based on very large numbers of structurally homologous proteins, i.e., the core of aspartyl proteases is very highly conserved, it is easy to introduce structural mistakes based on sequence misalignment, especially when there is low sequence identity.…”

Section: Homology Modelsmentioning

confidence: 99%

“…A crystal structure (PDB entry 2EWY) of BACE-2 [Ostermann et al, 2006] reveals a very similar active site to BACE-1, including the unique R235. While residue changes in the active site appear to be either conservative or compensatory (see Fig.…”

Section: Selectivitymentioning

confidence: 99%

“…This is nicely demonstrated by the identification of one of the most potent peptidomimetics, L-685458, which happened to have the correct epimeric configuration for the hydroxyl group but it was only subsequently shown that the other epimer had over 500-fold lower activity [Shearman et al, 2000]. The development of peptidomimetics is now mainly for use as tool [Hong et al, 2000] and BACE-2 (2EWY, orange) [Ostermann et al, 2006] highlighting the differences in active site residues via the notation BACE-1 -BACE-2. The structure of OM99-2, bound in the active site of BACE-1, is depicted for reference.…”

Section: C-secretasementioning

confidence: 99%

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Structure and modeling in the design of β‐ and γ‐secretase inhibitors

Holloway

Hunt

McGaughey

2009

Drug Development Research

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This review discusses the involvement of structure and modeling in the design of b-secretase (BACE-1) and g-secretase inhibitors as putative Alzheimer's Disease therapeutics. The early and broad availability of structural information for BACE-1, a membrane-tethered aspartyl protease, has led to the use of in silico methods in the overall design and optimization process. However, for g-secretase, an integral membrane protein, the lack of a detailed 3D structure has limited the application of computational methods. Drug Dev Res 70 : 70-93, 2009.

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“…Up to now, crystal structure of the BACE-1 enzyme in complex with the different inhibitors have established its different binding subsites, i.e., S1 subsites include Leu30, Phe108, Typ115, and Ile118; S2 subsites include Arg235, Gln12, and Asn233; S3 subsites include Ala335, Ile110, and Ser113; S1' subsites include Lys224 and Thr329; and S2' subsites include Ile126 and Arg128 [34]. In this section, B8 in Table 1 was chosen as an example to characterize the binding mode with BACE-1.…”

Section: 2 Binding Mode With Bace-1mentioning

confidence: 99%

MTDLs Design on AChE (Acetylcholinesterase) and β-Secretase (BACE-1): 3D-QSAR and Molecular Docking Studies

Shi¹,

Tu²,

Sheng³

et al. 2015

JPP

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To find promising new multitargeted AD (Alzheimer's disease) inhibitors, the 3D-QSAR (three-dimensional quantitative structure-activity relationship) model for 32 AD inhibitors was established by using the CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity index analysis) methods. Results showed that the CoMFA and CoMSIA models were constructed successfully with a good cross-validated coefficient (q 2 ) and a non-cross-validated coefficient (R 2 ), and the binding modes obtained by molecular docking were in agreement with the 3D-QSAR results, which suggests that the present 3D-QSAR model has good predictive capability to guide the design and structural modification of novel multitargeted AD inhibitors. Meanwhile, we found that one side of inhibitory molecule should be small group so that it would be conductive to enter the gorge to interact with the catalytic active sites of AChE (acetylcholinesterase), and the other side of inhibitory molecule should be large group so that it would be favorable for interaction with the peripheral anionic site of AChE. Furthermore, based on the 3D-QSAR model and the binding modes of AChE and β-secretase (BACE-1), the designed molecules could both act on dual binding sites of AChE (catalytic and peripheral sites) and dual targets (AChE and BACE-1). We hope that our results could provide hints for the design of new multitargeted AD derivatives with more potency and selective activity.

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Crystal Structure of Human BACE2 in Complex with a Hydroxyethylamine Transition-state Inhibitor

Cited by 53 publications

References 37 publications

Levels of β-Secretase (BACE1) in Cerebrospinal Fluid as a Predictor of Risk in Mild Cognitive Impairment

Levels of β-Secretase (BACE1) in Cerebrospinal Fluid as a Predictor of Risk in Mild Cognitive Impairment

Structure and modeling in the design of β‐ and γ‐secretase inhibitors

MTDLs Design on AChE (Acetylcholinesterase) and β-Secretase (BACE-1): 3D-QSAR and Molecular Docking Studies

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