Department of Biochemistry
Structure of Macromolecular Machines using X-ray Crystallography and Electron Microscopy; Nonribosomal Peptide Synthetases
Francesco Bellini Life Sciences Building
3649 Promenade Sir William Osler
Office: Room 465; Lab: Room 457-470
Montreal, QC H3G 0B1
Tel: 514-398-2331; Lab: 514-398-3278
martin.schmeing [at] mcgill.ca
Schmeing Lab Web Page
2009 – Postdoc, LMB Cambridge
2004 – PhD, Yale University
In the news:
The Schmeing lab is interested in large macromolecular machines that perform important cellular processes. These enzymes often require supramolecular organization and complex architecture to function. For example, some enzymes use more than 100,000 atoms to make peptide bonds, while the proteases that break these bonds can be very small. Of course, these assemblies require regulation, processivity and fidelity, which contribute to their increased size. Our lab investigates both the manner by which cellular machines achieve these roles, and the mechanisms of their principal functions. To do this, we combine X-ray crystallography, electron microscopy and biochemical techniques.
Our main subject of study is nonribosomal peptide synthetases (NRPS). NRPSs are large macromolecular machines that catalyze peptide bond formation. Instead of making proteins, these megaenzymes produce a large variety of small molecules with important and diverse biological activity. For example, NRPSs synthesize anti-fungals, anti-bacterials, anti-virals, anti-tumourigenics, siderophores, and immunosuppressants including well-known compounds such as penicillin and cyclosporin. NRPSs use assembly line logic, with moving parts and dedicated active sites for each amino acid added to the peptide. NRPSs can be over 2 megadaltons in mass and are nature’s largest (and most fun!) enzymes.
Structures of a dimodular nonribosomal peptide synthetase reveal conformational flexibility. *Reimer JM, *Eivaskhani M, Harb I, Guarné A, Weigt M, Schmeing TM. Science. 2019 Nov 8; 366(6466).
Trapping biosynthetic acyl-enzyme intermediates with encoded 2,3-diaminopropionic acid. *Huguenin-Dezot N, *Alonzo DA, Heberlig GW, Mahesh M, Nguyen DP, Dornan MH, Boddy CN, **Schmeing TM, **Chin JW. Nature. 2019 Jan; 565(7737): 112-117.
X-ray crystallography and electron microscopy of cross- and multi-module nonribosomal peptide synthetase proteins reveal a flexible architecture. Tarry MJ, Haque AS, Bui KH, Schmeing TM. X. Structure. 2017 May 2;25(5):783-793.
Structural and mutational analysis of the nonribosomal peptide synthetase heterocyclization domain provides insight into catalysis. Bloudoff K, Fage CD, Marahiel MA, Schmeing TM. Proc Natl Acad Sci USA. 2017 Jan 3;114(1):95-100.
Chemical Probes Allow Structural Insight into the Condensation Reaction of Nonribosomal Peptide Synthetases. Bloudoff K, Alonzo DA, Schmeing TM. Cell Chem Biol. 2016 Mar 17;23(3).
Synthetic cycle of the initiation module of a formylating nonribosomal peptide synthetase. Reimer JM, Aloise MN, Harrison PM, Schmeing TM. Nature. 2016 Jan 14;529(7585).
Synthetase Suggest Conformational Changes during the Synthetic Cycle of Nonribosomal Peptide Synthetases. Bloudoff K, Rodionov D, Schmeing TM. Crystal Structures of the First Condensation Domain of CDA J Mol Biol. 2013 Sep 9;425(17):3137-50.
The crystal structure of the ribosome bound to EF-Tu and tRNA. Schmeing TM*, Voorhees RM*, Kelley AC, Gao YG, Murphy FV, Weir JR, Ramakrishnan V. Science. 2009, Oct 30; 326(5953):688-94. PMID: 19833920
What recent ribosome structures have revealed about the mechanism of translation. Schmeing TM, Ramakrishnan, V. Nature. 2009, Oct 29; 461(7268):1234-1242. PMID: 19838167
An induced fit mechanism to promote peptide bond formation and exclude hydrolysis of peptidyl-tRNA. Schmeing TM, Huang KS, Strobel SA, Steitz TA. Nature. 2005 Nov 24;438(7067):520-4. PMID: 16306996