Premium
Unique GMP‐binding site in Mycobacterium tuberculosis guanosine monophosphate kinase
Author(s) -
Hible Guillaume,
Christova Petya,
Renault Louis,
Seclaman Edward,
Thompson Andrew,
Girard Eric,
MunierLehmann Hélène,
Cherfils Jacqueline
Publication year - 2005
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20662
Subject(s) - chemistry , biochemistry , guanosine , binding site , nucleoside , kinase , stereochemistry , docking (animal) , nursing , medicine
Bacterial nucleoside monophosphate (NMP) kinases, which convert NMPs to nucleoside diphosphates (NDP), are investigated as potential antibacterial targets against pathogenic bacteria. Herein, we report the biochemical and structural characterization of GMP kinase from Mycobacterium tuberculosis (GMPK Mt ). GMPK Mt is a monomer with an unusual specificity for ATP as a phosphate donor, a lower catalytic efficiency compared with eukaryotic GMPKs, and it carries two redox‐sensitive cysteines in the central CORE domain. These properties were analyzed in the light of the high‐resolution crystal structures of unbound, GMP‐bound, and GDP‐bound GMPK Mt . The latter structure was obtained in both an oxidized form, in which the cysteines form a disulfide bridge, and a reduced form which is expected to correspond to the physiological enzyme. GMPK Mt has a modular domain structure as most NMP kinases. However, it departs from eukaryotic GMPKs by the unusual conformation of its CORE domain, and by its partially open LID and GMP‐binding domains which are the same in the apo‐, GMP‐bound, and GDP‐bound forms. GMPK Mt also features a unique GMP binding site which is less close‐packed than that of mammalian GMPKs, and in which the replacement of a critical tyrosine by a serine removes a catalytic interaction. In contrast, the specificity of GMPK Mt for ATP may be a general feature of GMPKs because of an invariant structural motif that recognizes the adenine base. Altogether, differences in domain dynamics and GMP binding between GMPK Mt and mammalian GMPKs should reveal clues for the design of GMPK Mt ‐specific inhibitors. Proteins 2006. © 2005 Wiley‐Liss, Inc.