High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The promising drug target N-myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly). Here, we present high-resolution human NMT1 structures co-crystallised with reactive cognate lipid and peptide substrates, revealing high-resolution snapshots of the entire catalytic mechanism from the initial to final reaction states. Structural comparisons, together with biochemical analysis, provide unforeseen details about how NMT1 reaches a catalytically competent conformation in which the reactive groups are brought into close proximity to enable catalysis. We demonstrate that this mechanism further supports efficient and unprecedented myristoylation of an N-terminal lysine side chain, providing evidence that NMT acts both as N-terminal-lysine and glycine myristoyltransferase.
Date Issued
2020-02-28
Date Acceptance
2020-02-04
Citation
Nature Communications, 2020, 11, pp.1-15
ISSN
2041-1723
Publisher
Nature Research (part of Springer Nature)
Start Page
1
End Page
15
Journal / Book Title
Nature Communications
Volume
11
Copyright Statement
© The Author(s) 2020. This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons licence, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons licence, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this licence, visit http://creativecommons.org/
licenses/by/4.0/
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons licence, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons licence, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this licence, visit http://creativecommons.org/
licenses/by/4.0/
Sponsor
Cancer Research UK
Cancer Research UK
Medicines for Malaria Venture
Identifier
https://www.nature.com/articles/s41467-020-14847-3
Grant Number
20183
C29637/A9913
RD/14/0015
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
BOUND MYRISTOYLCOA
MALARIA
COA
LEISHMANIASIS
HYDROLYSIS
INHIBITORS
PRECURSOR
ACYLATION
REVEALS
TARGET
Acyltransferases
Catalysis
Catalytic Domain
Coenzyme A
Crystallography, X-Ray
Glycine
Humans
Kinetics
Lysine
Mutation
Myristic Acid
Protein Structure, Secondary
Protein Structure, Tertiary
Structure-Activity Relationship
Substrate Specificity
Humans
Coenzyme A
Acyltransferases
Myristic Acid
Lysine
Glycine
Crystallography, X-Ray
Catalytic Domain
Protein Structure, Secondary
Protein Structure, Tertiary
Structure-Activity Relationship
Substrate Specificity
Kinetics
Mutation
Catalysis
Publication Status
Published
Article Number
1132
Date Publish Online
2020-02-28