PDBsum entry 2bxe

Transport protein

PDB id: 2bxe

Contents

Protein chain

569 a.a. *

Ligands

1FL ×6

* Residue conservation analysis

PDB id:

2bxe

Name:

Transport protein

Title:

Human serum albumin complexed with diflunisal

Structure:

Serum albumin. Chain: a, b. Synonym: human serum albumin. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: plasma. Expressed in: pichia pastoris. Expression_system_taxid: 4922

Resolution:

2.95Å R-factor: 0.226 R-free: 0.270

Authors:

J.Ghuman,P.A.Zunszain,I.Petitpas,A.A.Bhattacharya,S.Curry

Key ref:

J.Ghuman et al. (2005). Structural basis of the drug-binding specificity of human serum albumin. J Mol Biol, 353, 38-52. PubMed id: 16169013 DOI: 10.1016/j.jmb.2005.07.075

Date:

26-Jul-05 Release date: 22-Sep-05

Protein chains

P02768  (ALBU_HUMAN) -  Albumin from Homo sapiens

Seq: 609 a.a.

Struc: 569 a.a.

DOI no: 10.1016/j.jmb.2005.07.075

J Mol Biol 353:38-52 (2005)

PubMed id: 16169013

Structural basis of the drug-binding specificity of human serum albumin.

J.Ghuman, P.A.Zunszain, I.Petitpas, A.A.Bhattacharya, M.Otagiri, S.Curry.

ABSTRACT

Human serum albumin (HSA) is an abundant plasma protein that binds a remarkably wide range of drugs, thereby restricting their free, active concentrations. The problem of overcoming the binding affinity of lead compounds for HSA represents a major challenge in drug development. Crystallographic analysis of 17 different complexes of HSA with a wide variety of drugs and small-molecule toxins reveals the precise architecture of the two primary drug-binding sites on the protein, identifying residues that are key determinants of binding specificity and illuminating the capacity of both pockets for flexible accommodation. Numerous secondary binding sites for drugs distributed across the protein have also been identified. The binding of fatty acids, the primary physiological ligand for the protein, is shown to alter the polarity and increase the volume of drug site 1. These results clarify the interpretation of accumulated drug binding data and provide a valuable template for design efforts to modulate the interaction with HSA.

Selected figure(s)

Figure 2.
Figure 2. Overview of HSA structure and omit maps. (a) Structure of HSA-diazepam. The protein is colour-coded by subdomain using a scheme that is maintained throughout. The diazepam is depicted in space-filling representation colour-coded by atom-type: carbon, pink; oxygen, red; nitrogen, blue; chlorine, gr. The rotated view on the right shows drug site 2 in the same orientation as drug site 1 in (c). (b) F[o] -F[c] simulated annealing omit map calculated in CNS50 with the diazepam molecule omitted from the phasing model and contoured at 2.75s. (c) Structure of HSA-myristate-phenylbutazone. Fatty acid molecules and phenylbutazone are depicted in space-filling representation with carbon atoms coloured grey and mid-blue, respectively. (d) F[o] -F[c] simulated annealing omit map calculated with the phenylbutazone molecule omitted from the phasing model and contoured at 2.75s. All Figures were prepared using PyMol.55

Figure 7.
Figure 7. Summary of the ligand binding capacity of HSA as defined by crystallographic studies to date. Ligands are depicted in space-filling representation; oxygen atoms are coloured red; all other atoms in fatty acids (myristic acid), other endogenous ligands (hemin, thyroxin) and drugs are coloured dark-grey, light grey and orange, respectively.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 353, 38-52) copyright 2005.

Figures were selected by the author.