Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors
Author(s)
Type
Journal Article
Abstract
The leishmaniases are a spectrum of global diseases of poverty associated with
immune dysfunction and are the cause of high morbidity. Despite the long
history of these diseases, no effective vaccine is available and the currently used
drugs are variously compromised by moderate efficacy, complex side effects and
the emergence of resistance. It is therefore widely accepted that new therapies
are needed. N-Myristoyltransferase (NMT) has been validated pre-clinically as
a target for the treatment of fungal and parasitic infections. In a previously
reported high-throughput screening program, a number of hit compounds with
activity against NMT from Leishmania donovani have been identified. Here,
high-resolution crystal structures of representative compounds from four hit
series in ternary complexes with myristoyl-CoA and NMT from the closely
related L. major are reported. The structures reveal that the inhibitors associate
with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA
and the catalytic -carboxylate of Leu421. Each inhibitor makes extensive
apolar contacts as well as a small number of polar contacts with the protein.
Remarkably, the compounds exploit different features of the peptide-binding
groove and collectively occupy a substantial volume of this pocket, suggesting
that there is potential for the design of chimaeric inhibitors with significantly
enhanced binding. Despite the high conservation of the active sites of the
parasite and human NMTs, the inhibitors act selectively over the host enzyme.
The role of conformational flexibility in the side chain of Tyr217 in conferring
selectivity is discussed.
immune dysfunction and are the cause of high morbidity. Despite the long
history of these diseases, no effective vaccine is available and the currently used
drugs are variously compromised by moderate efficacy, complex side effects and
the emergence of resistance. It is therefore widely accepted that new therapies
are needed. N-Myristoyltransferase (NMT) has been validated pre-clinically as
a target for the treatment of fungal and parasitic infections. In a previously
reported high-throughput screening program, a number of hit compounds with
activity against NMT from Leishmania donovani have been identified. Here,
high-resolution crystal structures of representative compounds from four hit
series in ternary complexes with myristoyl-CoA and NMT from the closely
related L. major are reported. The structures reveal that the inhibitors associate
with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA
and the catalytic -carboxylate of Leu421. Each inhibitor makes extensive
apolar contacts as well as a small number of polar contacts with the protein.
Remarkably, the compounds exploit different features of the peptide-binding
groove and collectively occupy a substantial volume of this pocket, suggesting
that there is potential for the design of chimaeric inhibitors with significantly
enhanced binding. Despite the high conservation of the active sites of the
parasite and human NMTs, the inhibitors act selectively over the host enzyme.
The role of conformational flexibility in the side chain of Tyr217 in conferring
selectivity is discussed.
Date Issued
2014-07-01
Date Acceptance
2014-06-04
Citation
IUCrJ, 2014, 1, pp.250-260
ISSN
2052-2525
Publisher
International Union of Crystallography: IUCrJ
Start Page
250
End Page
260
Journal / Book Title
IUCrJ
Volume
1
Copyright Statement
© 2014 The Authors. Creative Commons Attribution License
License URL
Subjects
Science & Technology
Physical Sciences
Technology
Chemistry, Multidisciplinary
Crystallography
Materials Science, Multidisciplinary
Chemistry
Materials Science
N-myristoyltransferase
inhibitor
ligand binding
Leishmania
drug discovery
CEREVISIAE MYRISTOYL-COA
POTENTIAL-DRUG TARGET
PLASMODIUM-FALCIPARUM
CANDIDA-ALBICANS
CRYPTOCOCCUS-NEOFORMANS
BOUND MYRISTOYLCOA
CRYSTAL-STRUCTURES
DISCOVERY
DESIGN
TRANSFERASE
Publication Status
Published