3HQJ

Structure-function analysis of Mycobacterium tuberculosis acyl carrier protein synthase (AcpS).

Summary for 3HQJ

• Entry DOI: 10.2210/pdb3hqj/pdb
• Descriptor: Holo-[acyl-carrier-protein] synthase, MAGNESIUM ION, COENZYME A, ... (4 entities in total)
• Functional Keywords: an/fold, structural genomics, israel structural proteomics center, ispc, cytoplasm, fatty acid biosynthesis, lipid synthesis, magnesium, metal-binding, transferase
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cytoplasm (By similarity): P0A4W8
• Total number of polymer chains: 1
• Total formula weight: 14952.39

Authors

Dym, O.,Albeck, S.,Peleg, Y.,Schwarz, A.,Shakked, Z.,Burstein, Y.,Zimhony, O.,Israel Structural Proteomics Center (ISPC) (deposition date: 2009-06-07, release date: 2009-09-15, Last modification date: 2023-09-06)

Primary citation

Dym, O.,Albeck, S.,Peleg, Y.,Schwarz, A.,Shakked, Z.,Burstein, Y.,Zimhony, O.
Structure-function analysis of the acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis.
J.Mol.Biol., 393:937-950, 2009

PubMed Abstract: We have solved the crystal structure of the acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis (Mtb) at 1.95 A resolution. AcpS, a 4-phosphopantetheinyl transferase, activates two distinct acyl carrier proteins (ACPs) that are present in fatty acid synthase (FAS) systems FAS-I and FAS-II, the ACP-I domain and the mycobacterial ACP-II protein (ACPM), respectively. Mtb, the causal agent of tuberculosis (TB), and all other members of the Corynebacterineae family are unique in possessing both FAS systems to produce and to elongate fatty acids to mycolic acids, the hallmark of mycobacterial cell wall. Various steps in this process are prime targets for first-line anti-TB agents. A comparison of the Mtb AcpS structure determined here with those of other AcpS proteins revealed unique structural features in Mtb AcpS, namely, the presence of an elongated helix followed by a flexible loop and a moderately electronegative surface unlike the positive surface common to other AcpSs. A structure-based sequence comparison between AcpS and its ACP substrates from various species demonstrated that the proteins of the Corynebacterineae family display high sequence conservation, forming a segregated subgroup of AcpS and ACPs. Analysis of the putative interactions between AcpS and ACPM from Mtb, based on a comparison with the complex structure from Bacillus subtilis, showed that the Mtb AcpS and ACPM lack the electrostatic complementarity observed in B. subtilis. Taken together, the common characteristic of the Corynebacterineae family is likely reflected in the participation of different residues and interactions used for binding the Mtb AcpS to ACP-I and ACPM. The distinct features and essentiality of AcpS, as well as the mode of interaction with ACPM and ACP-I in Mtb, could be exploited for the design of AcpS inhibitors, which, similarly to other inhibitors of fatty acid synthesis, are expected to be effective anti-TB-specific drugs.

PubMed: 19733180
DOI: 10.1016/j.jmb.2009.08.065

Experimental method

X-RAY DIFFRACTION (1.95 Å)