PDBsum entry 2fa3

Transferase

PDB id: 2fa3

Contents

Protein chain

450 a.a.

Ligands

ACO

Waters ×133

References listed in PDB file

Key reference

Title

Structural basis for the design of potent and species-Specific inhibitors of 3-Hydroxy-3-Methylglutaryl CoA synthases.

Authors

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

Ref.

Proc Natl Acad Sci U S A, 2006, 103, 11491-11496. [DOI no: 10.1073/pnas.0604935103]

PubMed id

16864776

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.

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.