Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A ° resolution

Céline Schalk-Hihi; Carsten Schubert; Richard Alexander; Shariff Bayoumy; Jose C. Clemente; Ingrid Deckman; Renee L. DesJarlais; Keli C. Dzordzorme; Christopher M. Flores; Bruce Grasberger; James K. Kranz; Frank Lewandowski; Li Liu; Hongchang Ma; Diane Maguire; Mark J. Macielag; Mark E. McDonnell; Tara Mezzasalma Haarlander; Robyn Miller; Cindy Milligan; Charles Reynolds; Lawrence C. Kuo

doi:10.1002/pro.596

Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A ° resolution

Céline Schalk-Hihi, Carsten Schubert, Richard Alexander, Shariff Bayoumy, Jose C. Clemente, Ingrid Deckman, Renee L. DesJarlais, Keli C. Dzordzorme, Christopher M. Flores, Bruce Grasberger, James K. Kranz, Frank Lewandowski, Li Liu, Hongchang Ma, Diane Maguire, Mark J. Macielag, Mark E. McDonnell, Tara Mezzasalma Haarlander, Robyn Miller, Cindy MilliganCharles Reynolds, Lawrence C. Kuo

Research output: Contribution to journal › Article › peer-review

117 Scopus citations

Abstract

A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form.

Original language	English
Pages (from-to)	670-683
Number of pages	14
Journal	Protein Science
Volume	20
Issue number	4
DOIs	https://doi.org/10.1002/pro.596
State	Published - Apr 2011
Externally published	Yes

Keywords

Cannabinoid receptor
Lid-domain
Monoglyceride lipase
Protein inhibitor complex

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Schalk-Hihi, C., Schubert, C., Alexander, R., Bayoumy, S., Clemente, J. C., Deckman, I., DesJarlais, R. L., Dzordzorme, K. C., Flores, C. M., Grasberger, B., Kranz, J. K., Lewandowski, F., Liu, L., Ma, H., Maguire, D., Macielag, M. J., McDonnell, M. E., Haarlander, T. M., Miller, R., ... Kuo, L. C. (2011). Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A ° resolution. Protein Science, 20(4), 670-683. https://doi.org/10.1002/pro.596

@article{e7f10f297e75472d9ce61670c4e47f25,

title = "Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A ° resolution",

abstract = "A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form.",

keywords = "Cannabinoid receptor, Lid-domain, Monoglyceride lipase, Protein inhibitor complex",

author = "C{\'e}line Schalk-Hihi and Carsten Schubert and Richard Alexander and Shariff Bayoumy and Clemente, {Jose C.} and Ingrid Deckman and DesJarlais, {Renee L.} and Dzordzorme, {Keli C.} and Flores, {Christopher M.} and Bruce Grasberger and Kranz, {James K.} and Frank Lewandowski and Li Liu and Hongchang Ma and Diane Maguire and Macielag, {Mark J.} and McDonnell, {Mark E.} and Haarlander, {Tara Mezzasalma} and Robyn Miller and Cindy Milligan and Charles Reynolds and Kuo, {Lawrence C.}",

year = "2011",

month = apr,

doi = "10.1002/pro.596",

language = "English",

volume = "20",

pages = "670--683",

journal = "Protein Science",

issn = "0961-8368",

publisher = "Wiley-Blackwell",

number = "4",

}

Schalk-Hihi, C, Schubert, C, Alexander, R, Bayoumy, S, Clemente, JC, Deckman, I, DesJarlais, RL, Dzordzorme, KC, Flores, CM, Grasberger, B, Kranz, JK, Lewandowski, F, Liu, L, Ma, H, Maguire, D, Macielag, MJ, McDonnell, ME, Haarlander, TM, Miller, R, Milligan, C, Reynolds, C & Kuo, LC 2011, 'Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A ° resolution', Protein Science, vol. 20, no. 4, pp. 670-683. https://doi.org/10.1002/pro.596

TY - JOUR

T1 - Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A ° resolution

AU - Schalk-Hihi, Céline

AU - Schubert, Carsten

AU - Alexander, Richard

AU - Bayoumy, Shariff

AU - Clemente, Jose C.

AU - Deckman, Ingrid

AU - DesJarlais, Renee L.

AU - Dzordzorme, Keli C.

AU - Flores, Christopher M.

AU - Grasberger, Bruce

AU - Kranz, James K.

AU - Lewandowski, Frank

AU - Liu, Li

AU - Ma, Hongchang

AU - Maguire, Diane

AU - Macielag, Mark J.

AU - McDonnell, Mark E.

AU - Haarlander, Tara Mezzasalma

AU - Miller, Robyn

AU - Milligan, Cindy

AU - Reynolds, Charles

AU - Kuo, Lawrence C.

PY - 2011/4

Y1 - 2011/4

N2 - A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form.

AB - A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form.

KW - Cannabinoid receptor

KW - Lid-domain

KW - Monoglyceride lipase

KW - Protein inhibitor complex

UR - http://www.scopus.com/inward/record.url?scp=79953202170&partnerID=8YFLogxK

U2 - 10.1002/pro.596

DO - 10.1002/pro.596

M3 - Article

C2 - 21308848

AN - SCOPUS:79953202170

SN - 0961-8368

VL - 20

SP - 670

EP - 683

JO - Protein Science

JF - Protein Science

IS - 4

ER -

Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A ° resolution

Abstract

Keywords

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