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3hqj

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3hqj, resolution 1.95Å ()
Sites: , , and
Ligands: ,
Gene: acpS, Rv2523c, MT2599, MTV009.08c (Mycobacterium tuberculosis)
Activity: [acyl-carrier-protein_synthase Holo-[acyl-carrier-protein] synthase], with EC number 2.7.8.7
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



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

Publication Abstract from PubMed

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.

Structure-function analysis of the acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis., Dym O, Albeck S, Peleg Y, Schwarz A, Shakked Z, Burstein Y, Zimhony O, J Mol Biol. 2009 Nov 6;393(4):937-50. Epub 2009 Sep 3. PMID:19733180

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

The crystal structure of acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis (Mtb) was solved at 1.95 Å. It crystallized as one per asymmetric unit. Since Mtb AcpS has biologically active trimeric arrangement, (in lime, blue, and orange) was constructed using the 3-fold crystallographic symmetry in the P23 space group. The 3′,5′-ADP moieties of the coenzyme A (CoA, colored magenta), are positioned in the cleft between each of two monomers forming three active sites within AcpS trimer. The is formed by the residues D9 (highly conserved), E58, L62, and S65 from monomer A and by R92, P93, R53, H116, and T115 from the neighboring monomer B. The residues labeled and shown as sticks (A and B in the brackets point on the name of the monomer). Hydrogen bonds are shown as dashed lines with interatomic distances in Å. The magnesium (Mg) atoms are shown in spacefill representation and colored in cyan. The CoA is shown in stick representation and colored magenta. Nitrogen and oxygen atoms of the CoA 3′,5′-ADP moiety and of the active site resudues are colored blue and red, respectively.

of the structures of the Mtb AcpS trimer (in lime, blue, and orange) and the B. subtilis AcpS trimer (1f7t, in red, cyan, and yellow) reveals that the Mtb AcpS structure is similar to those of other members of group I phosphopantetheine transferase (PPT) family. The is that the extended α3 helix of Mtb AcpS has open conformation. Such open conformation permits to the extended loop of one monomer (lime) to interact with adjacent monomer (blue). The considerably shorter α3 of one B. subtilis AcpS monomer (red) has closed conformation and this doesn't allow interaction with the neighboring monomer (cyan).

The B. subtilis AcpS trimer (1f80) three molecules of the acyl carrier protein (ASP). The interactions between B. subtilis AcpS and ACP are predominantly . The B. subtilis AcpS (white) is shown in spacefill representation, the agrinines, lysines, and histidines are colored blue, while aspartates and glutamates are colored red. The ACP molecule (lime) is shown in ribbon representation with aspartates and glutamates as sticks and colored red. The B. subtilis AcpS has large with ASP. of Mtb AcpS surface using the similar orientation as B. subtilis AcpS, shows a moderate electronegative nature in the putative ACP binding site near the ASP 15. The Mtb ASPM structure (1klp, corresponding to ACP) demonstrates considerably lower negative charge. So, the electrostatic interactions between Mtb AcpS and ASPM are, probably, less important.


About this Structure

3HQJ is a 1 chain structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.

Reference

  • 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. 2009 Nov 6;393(4):937-50. Epub 2009 Sep 3. PMID:19733180

Page seeded by OCA on Wed Sep 16 09:11:05 2009

Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky, OCA

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