Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products

Nicolet, Yvain; Lockridge, Oksana; Masson, Patrick; Fontecilla‐Camps, Juan C.; Nachon, Florian

doi:10.1074/jbc.m210241200

Cited by 720 publications

(612 citation statements)

References 42 publications

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“…Ekstrom et al, 2002;Evans et al, 2002;Gadola et al, 2002;Hall et al, 2002;Matern et al, 2003;Nicolet et al, 2003;Zavala-Ruiz et al, 2003;Dong et al, 2004).…”

Section: Testing In X-ray Refinementunclassified

PRODRG: a tool for high-throughput crystallography of protein–ligand complexes

Schüttelkopf

Aalten

2004

Acta Crystallogr D Biol Crystallogr

4,600

3,269

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The small-molecule topology generator PRODRG is described, which takes input from existing coordinates or various two-dimensional formats and automatically generates coordinates and molecular topologies suitable for X-ray re®nement of protein±ligand complexes. Test results are described for automatic generation of topologies followed by energy minimization for a subset of compounds from the Cambridge Structural Database, which shows that, within the limits of the empirical GROMOS87 force ®eld used, structures with good geometries are generated. X-ray re®nement in X-PLOR/CNS, REFMAC and SHELX using PRODRGgenerated topologies produces results comparable to re®ne-ment with topologies from the standard libraries. However, tests with distorted starting coordinates show that PRODRG topologies perform better, both in terms of ligand geometry and of crystallographic R factors.

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“…Ekstrom et al, 2002;Evans et al, 2002;Gadola et al, 2002;Hall et al, 2002;Matern et al, 2003;Nicolet et al, 2003;Zavala-Ruiz et al, 2003;Dong et al, 2004).…”

Section: Testing In X-ray Refinementunclassified

PRODRG: a tool for high-throughput crystallography of protein–ligand complexes

Schüttelkopf

Aalten

2004

Acta Crystallogr D Biol Crystallogr

4,600

3,269

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“…The inhibited enzyme was crystallized by the hanging drop method as described (12). Crystals grew to 0.5 × 0.5 × 0.3 mm in one week at 20°C.…”

Section: Crystals Of Nonaged Echothiophate-inhibited Hbchementioning

confidence: 99%

Role of Water in Aging of Human Butyrylcholinesterase Inhibited by Echothiophate: The Crystal Structure Suggests Two Alternative Mechanisms of Aging^,

et al. 2005

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Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves the residues His438 and Glu197 that are proximal to the active-site serine (Ser198). The mechanism of aging is known in detail for the nerve gases soman, sarin, and tabun as well as the pesticide metabolite isomalathion. Aging of soman-and sarin-inhibited acetylcholinesterase occurs by C-O bond cleavage, whereas that of tabun-and isomalathion-inhibited acetylcholinesterase occurs by P-N and P-S bond cleavage, respectively. In this work, the crystal structures of hBChE inhibited by the ophthalmic reagents echothiophate (nonaged and aged) and diisopropylfluorophosphate (aged) were solved and refined to 2.1, 2.25, and 2.2 Å resolution, respectively. No appreciable shift in the position of the catalytic triad histidine was observed between the aged and nonaged conjugates of hBChE. This absence of shift contrasts with the aged and nonaged crystal structures of Torpedo californica acetylcholinesterase inhibited by the nerve agent VX. The nonaged hBChE structure shows one water molecule interacting with Glu197 and the catalytic triad histidine (His438). Interestingly, this water molecule is ideally positioned to promote aging by two mechanisms: breaking either a C-O bond or a P-O bond. Pesticides and certain stereoisomers of nerve agents are expected to undergo aging by breaking the P-O bond.

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“…This gorge is lined by 14 conserved aromatic amino acids and hence frequently called the 'aromatic gorge' [8]. The recently solved crystal structure of the BChE enzyme [9] was shown to be very similar to that of Torpedo californica AChE. However, several aromatic amino acids, lining the gorge of the AChE, have been replaced in BChE by hydrophobic analogues.…”

Section: Introductionmentioning

confidence: 99%

New natural cholinesterase inhibiting and calcium channel blocking quinoline alkaloids

Atta-ur-Rahman

Khalid

Sultana

et al. 2006

Journal of Enzyme Inhibition and Medicinal Chemistry

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During this study, one new coumarin; 7-O-b-D-glucopyranoside-2H-1-benzopyran-2-one (1) and three quinoline alkaloids; 3-hydroxy, 2, 2, 6-trimethyl -3, 4, 5, 6-tetrahydro-2H-pyrano[3,2-c] quinoline 5-one (2), ribalinine (3) and methyl isoplatydesmine (4) were isolated from the aerial parts of Skimmia laureola and their structures established by spectroscopic studies. Compounds 2-4 were found to be linear mixed type inhibitors of acetylcholinesterase (K i ¼ 110.0, 30.0 and 30.0 mM, respectively). Compounds 2 and 3 were also found to be linear mixed type inhibitors of butyrylcholinesterase, while compound 4 was a noncompetitive inhibitor of the enzyme (K i ¼ 90.0, 70.0 and 19.0 mM, respectively). The inhibition of acetyl-and butyryl-cholinesterase enzymes persists as the most promising therapeutic strategy for activating the impaired cholinergic functions in Alzheimer's disease and related dementias.Compound 4 also showed dose-dependent spasmolytic activity in the isolated rabbit jejunum intestinal preparation by relaxing the spontaneous (EC 50 ¼ 0.1 mg/mL) and K þ -induced contractions (EC 50 ¼ 0.4 mg/mL), suggesting that the spasmolytic effect of compound 4 is mediated through the blockade of voltage-dependent Ca 2 þ channels.

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Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products

Cited by 720 publications

References 42 publications

PRODRG: a tool for high-throughput crystallography of protein–ligand complexes

PRODRG: a tool for high-throughput crystallography of protein–ligand complexes

Role of Water in Aging of Human Butyrylcholinesterase Inhibited by Echothiophate: The Crystal Structure Suggests Two Alternative Mechanisms of Aging^,

New natural cholinesterase inhibiting and calcium channel blocking quinoline alkaloids

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Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products

Cited by 720 publications

References 42 publications

PRODRG: a tool for high-throughput crystallography of protein–ligand complexes

PRODRG: a tool for high-throughput crystallography of protein–ligand complexes

Role of Water in Aging of Human Butyrylcholinesterase Inhibited by Echothiophate: The Crystal Structure Suggests Two Alternative Mechanisms of Aging,

New natural cholinesterase inhibiting and calcium channel blocking quinoline alkaloids

Contact Info

Product

Resources

About

Role of Water in Aging of Human Butyrylcholinesterase Inhibited by Echothiophate: The Crystal Structure Suggests Two Alternative Mechanisms of Aging^,