Effects of Distal Mutations on the Structure, Dynamics and Catalysis of Human Monoacylglycerol Lipase.


Abstract

An understanding of how conformational dynamics modulates function and catalysis of human monoacylglycerol lipase (hMGL), an important pharmaceutical target, can facilitate the development of novel ligands with potential therapeutic value. Here, we report the discovery and characterization of an allosteric, regulatory hMGL site comprised of residues Trp-289 and Leu-232 that reside over 18 Å away from the catalytic triad. These residues were identified as critical mediators of long-range communication and as important contributors to the integrity of the hMGL structure. Nonconservative replacements of Trp-289 or Leu-232 triggered concerted motions of structurally distinct regions with a significant conformational shift toward inactive states and dramatic loss in catalytic efficiency of the enzyme. Using a multimethod approach, we show that the dynamically relevant Trp-289 and Leu-232 residues serve as communication hubs within an allosteric protein network that controls signal propagation to the active site, and thus, regulates active-inactive interconversion of hMGL. Our findings provide new insights into the mechanism of allosteric regulation of lipase activity, in general, and may provide alternative drug design possibilities.

Submission Details

ID: 2DsQtAYM3

Submitter: Shu-Ching Ou

Submission Date: Jan. 17, 2019, 2:35 p.m.

Version: 1

Publication Details
Tyukhtenko S;Rajarshi G;Karageorgos I;Zvonok N;Gallagher ES;Huang H;Vemuri K;Hudgens JW;Ma X;Nasr ML;Pavlopoulos S;Makriyannis A,Sci Rep (2018) Effects of Distal Mutations on the Structure, Dynamics and Catalysis of Human Monoacylglycerol Lipase. PMID:29379013
Additional Information

W35->W53, W289->W307, R293->R311, L232->L250

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
3PE6 2011-03-02 1.35 Crystal Structure of a soluble form of human MGLL in complex with an inhibitor
5ZUN 2018-10-17 1.35 Crystal structure of human monoacylglycerol lipase in complex with compound 3l
6BQ0 2018-03-14 2.0 Structure of human monoacylglycerol lipase bound to a covalent inhibitor
3JW8 2010-01-26 2.1 Crystal structure of human mono-glyceride lipase
3HJU 2009-12-08 2.2 Crystal structure of human monoglyceride lipase
6AX1 2017-12-27 2.26 Structure of human monoacylglycerol lipase bound to a covalent inhibitor
4UUQ 2015-01-21 2.36 Crystal structure of human mono-glyceride lipase in complex with SAR127303
3JWE 2010-01-26 2.7 Crystal structure of human mono-glyceride lipase in complex with SAR629

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
200.0 A,B Monoglyceride lipase Q99685 MGLL_HUMAN