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.
ID: 2DsQtAYM3
Submitter: Shu-Ching Ou
Submission Date: Jan. 17, 2019, 2:35 p.m.
Version: 1
W35->W53, W289->W307, R293->R311, L232->L250
Number of data points | 34 |
Proteins | Monoglyceride lipase |
Unique complexes | 6 |
Assays/Quantities/Protocols | Experimental Assay: Km ; Experimental Assay: kcat ; Derived Quantity: Relative kcat/Km ; Derived Quantity: kcat/Km ; Derived Quantity: SD of Km ; Derived Quantity: SD of kcat |
Libraries | Variants for hMGL_2-AG |
Colors: | D | E | R | H | K | S | T | N | Q | A | V | I | L | M | F | Y | W | C | G | P |
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Structure ID | Release Date | Resolution | Structure Title |
---|---|---|---|
3HJU | 2009-05-22T00:00:00+0000 | 2.2 | Crystal structure of human monoglyceride lipase |
3JW8 | 2009-09-18T00:00:00+0000 | 2.1 | Crystal structure of human mono-glyceride lipase |
3JWE | 2009-09-18T00:00:00+0000 | 2.7 | Crystal structure of human mono-glyceride lipase in complex with SAR629 |
3PE6 | 2010-10-25T00:00:00+0000 | 1.35 | Crystal Structure of a soluble form of human MGLL in complex with an inhibitor |
4UUQ | 2014-07-30T00:00:00+0000 | 2.36 | Crystal structure of human mono-glyceride lipase in complex with SAR127303 |
5ZUN | 2018-05-08T00:00:00+0000 | 1.35 | Crystal structure of human monoacylglycerol lipase in complex with compound 3l |
6AX1 | 2017-09-06T00:00:00+0000 | 2.26 | Structure of human monoacylglycerol lipase bound to a covalent inhibitor |
6BQ0 | 2017-11-27T00:00:00+0000 | 2.0 | Structure of human monoacylglycerol lipase bound to a covalent inhibitor |
7L4T | 2020-12-21T00:00:00+0000 | 2.2 | Crystal structure of human monoacylglycerol lipase in complex with compound 1 |
7L4U | 2020-12-21T00:00:00+0000 | 2.25 | Crystal structure of human monoacylglycerol lipase in complex with compound 1h |
Percent Identity | Matching Chains | Protein | Accession | Entry Name |
---|---|---|---|---|
200.0 | A,B | Monoglyceride lipase | Q99685 | MGLL_HUMAN |