PDBsum entry 2fa3

Transferase

PDB id: 2fa3

Contents

Protein chain

450 a.a. *

Ligands

ACO

Waters ×133

* Residue conservation analysis

PDB id:

2fa3

Name:

Transferase

Title:

Hmg-coa synthase from brassica juncea in complex with acetyl-coa and acetyl-cys117.

Structure:

Hmg-coa synthase. Chain: a. Engineered: yes

Source:

Brassica juncea. Organism_taxid: 3707. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Dimer (from PDB file)

Resolution:

2.52Å R-factor: 0.181 R-free: 0.282

Authors:

F.Pojer,J.L.Ferrer,S.B.Richard,J.P.Noel

Key ref:

F.Pojer et al. (2006). Structural basis for the design of potent and species-specific inhibitors of 3-hydroxy-3-methylglutaryl CoA synthases. Proc Natl Acad Sci U S A, 103, 11491-11496. PubMed id: 16864776 DOI: 10.1073/pnas.0604935103

Date:

06-Dec-05 Release date: 25-Jul-06

Protein chain

Q9M6U3  (Q9M6U3_BRAJU) -  Hydroxymethylglutaryl-CoA synthase from Brassica juncea

Seq: 461 a.a.

Struc: 450 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.3.3.10 - hydroxymethylglutaryl-CoA synthase.
• Pathway: Mevalonate Biosynthesis
• Reaction: acetoacetyl-CoA + acetyl-CoA + H2O = (3S)-3-hydroxy-3-methylglutaryl-CoA + CoA + H⁺

acetoacetyl-CoA + acetyl-CoA (Bound ligand (Het Group name = ACO) corresponds exactly) + H2O = (3S)-3-hydroxy-3-methylglutaryl-CoA + CoA + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1073/pnas.0604935103

Proc Natl Acad Sci U S A 103:11491-11496 (2006)

PubMed id: 16864776

Structural basis for the design of potent and species-specific inhibitors of 3-hydroxy-3-methylglutaryl CoA synthases.

F.Pojer, J.L.Ferrer, S.B.Richard, D.A.Nagegowda, M.L.Chye, T.J.Bach, J.P.Noel.

ABSTRACT

3-Hydroxy-3-methylglutaryl CoA synthase (HMGS) catalyzes the first committed step in the mevalonate metabolic pathway for isoprenoid biosynthesis and serves as an alternative target for cholesterol-lowering and antibiotic drugs. We have determined a previously undescribed crystal structure of a eukaryotic HMGS bound covalently to a potent and specific inhibitor F-244 [(E,E)-11-[3-(hydroxymethyl)-4-oxo-2-oxytanyl]-3,5,7-trimethyl-2,4-undecadienenoic acid]. Given the accessibility of synthetic analogs of the F-244 natural product, this inhibited eukaryotic HMGS structure serves as a necessary starting point for structure-based methods that may improve the potency and species-specific selectivity of the next generation of F-244 analogs designed to target particular eukaryotic and prokaryotic HMGS.

Selected figure(s)

Figure 3.
Fig. 3. Overview of HMGS in complex with F-244. (A) Electrostatic surface of HMGS covalently bound to ring-opened F-244. Color-coding is identical to Fig. 2A. The inhibitor F-244 does not occupy the same part of the pantothenate-binding tunnel as the CoA tail shown in Fig. 2A. (B) Stereoview of the HMGS active site for the ring-opened F-244 covalent complex. Color-coding and map calculations are identical to Fig. 2B. The first eight carbons of the acyl tail of F-244 are well ordered; however, the position of the remaining six carbons display much weaker electron density as the tail protrudes out of the active site entrance. (C) Close-up view of the HMGS active site for the ring-opened F-244 covalent complex. The SIGMAA-weighted 2F[o] - F[c] electron density map is shown in blue, contoured at 1 . A H-bond between Glu-83 and the 2-hydroxymethyl moiety of ring-opened F-244 is shown as rendered green cylinders.

Figure 4.
Fig. 4. Close-up view of F-244 covalently modifying the BjHMGS1 active site and a posited reaction mechanism based on the F-244 complex. (A) Secondary structure is shown as ribbons colored as in Fig. 1. Side chains and F-244 are depicted as half-colored bonds with red for oxygen, blue for nitrogen, and gold and gray for carbons on F-244 and HMGS side chains, respectively. The oxygen atoms of the ring-opened form of F-244 form H-bonds (green dashes) with Glu-83, His-247, and Asn-326 through a water molecule (red sphere) and backbone amides of Ser-359 and Cys-117. (B) Schematic representation of F-244 tethered to Cys-117 highlighting all intermolecular interactions. H-bonds are depicted as green dashes. Orange half circles depict van der Waals contacts with dashed curves specifying residues sitting behind the plane formed by F-244. (C) Putative reaction mechanism of HMGS. The proposed role of Glu-83 in the last hydrolytic step necessary for release of HMG-CoA is shown in a yellow box. The residues implicated in formation of the oxyanion hole are depicted in green, and H-bonds are shown as dashed bonds.

Figures were selected by an automated process.