PDBsum entry 2v6d

Transport protein

PDB id: 2v6d

Contents

Protein chain

342 a.a.

Ligands

PDN

Waters ×174

Obsolete entry

PDB id:

2v6d

Name:

Transport protein

Title:

Structure of corticosteroid-binding globulin in complex with cortisol

Structure:

Cortocosteroid-binding globulin. Synonym: cbg,transcortin,serpin a6. Chain: a. Fragment: residues 27-396. Mutation: yes: engineered: yes

Source:

Expressed in: escherichia coli. Rattus norvegicus. Rat. Organ: liver. Cell: extracellular

Resolution:

1.93Å R-factor: 0.214 R-free: 0.265

Authors:

M.A.Klieber,Y.A.Muller

Key ref:

M.A.Klieber et al. (2007). Corticosteroid-binding Globulin, a Structural Basis for Steroid Transport and Proteinase-triggered Release. J Biol Chem, 282, 29594-29603. PubMed id: 17644521 DOI: 10.1074/jbc.M705014200

Date:

16-Jul-07 Release date: 07-Aug-07

Protein chain

P31211  (CBG_RAT) -  Corticosteroid-binding globulin from Rattus norvegicus

Seq: 396 a.a.

Struc: 342 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1074/jbc.M705014200

J Biol Chem 282:29594-29603 (2007)

PubMed id: 17644521

Corticosteroid-binding Globulin, a Structural Basis for Steroid Transport and Proteinase-triggered Release.

M.A.Klieber, C.Underhill, G.L.Hammond, Y.A.Muller.

ABSTRACT

Corticosteroid-binding globulin (CBG) is a serine proteinase inhibitor (serpin) family member that transports glucocorticoids in blood and regulates their access to target cells. The 1.9A crystal structure of rat CBG shows that its steroid-binding site resembles the thyroxin-binding site in the related serpin, thyroxin-binding globulin, and mutagenesis studies have confirmed the contributions of key residues that constitute the steroid-binding pocket. Unlike thyroxin-bound thyroxin-binding globulin, the cortisol-bound CBG displays an "active" serpin conformation with the proteinase-sensitive, reactive center loop (RCL) fully expelled from the regulatory beta-sheet A. Moreover, the CBG structure allows us to predict that complete insertion of the proteolytically cleaved RCL into the serpin fold occurs in concert with a displacement and unwinding of helix D that would disrupt the steroid-binding site. This allosteric coupling between RCL positioning and occupancy of the CBG steroid-binding site, which resembles the ligand (glycosamino-glycan)-dependent activation of the thrombin inhibitory serpins heparin cofactor II and anti-thrombin RCLs, ensures both optimal recognition of CBG by target proteinases and efficient release of steroid to sites of action.

Selected figure(s)

Figure 1.
FIGURE 1. Crystal structure of rat CBG. A and B, ribbon representation of rat CBG viewed from two different angles. Secondary structure elements are named according to the common serpin nomenclature. The -sheets A, B, and C are colored in red, green, and blue, respectively. The trace of the residues of the RCL not visible in electron density maps (residues 329-338) is modeled by a dashed line. The steroid (cortisol) is bound on top of sheet B and shown in yellow. C, close-up of cortisol in the steroid-binding site. D, representative portion of the final [A]-weighted 2F[o] - F[c] electron density map contoured at 1.0 and showing cortisol with the surrounding residues Arg^10 and Trp^362.

Figure 3.
FIGURE 3. Hormone binding to CBG. A, stereo representation of the CBG (blue) steroid-binding site. B, schematic depiction of the interactions between CBG and cortisol. Water molecules are shown as red dots, hydrophobic interactions are shown with dashed lines, and polar interactions are shown with dotted lines in A and B. C, for comparison, thyroxin-binding site in TBG (Protein Data Bank code 2ceo). Note that similar residues are involved in binding cortisol in CBG and thyroxin in TBG. D, mapping of three different serpin ligand-binding sites onto the CBG surface (in blue). Cortisol is shown in yellow, and thyroxin is in green, as bound to TBG. Heparin (in orange) binds on top of helix D in antithrombin (Protein Data Bank code 1e03) close to the shared ligand-binding site in TBG and CBG.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 29594-29603) copyright 2007.

Figures were selected by the author.