PDBsum entry 3cml

Membrane protein

PDB id: 3cml

Contents

Protein chain

317 a.a. *

Waters ×98

* Residue conservation analysis

PDB id:

3cml

Name:

Membrane protein

Title:

Crystal structure of the dbl3x domain of the plasmodium falcipurum var2csa protein

Structure:

Erythrocyte membrane protein 1. Chain: a. Fragment: dbl3x domain (unp residues 1220-1580). Engineered: yes

Source:

Plasmodium falciparum. Malaria parasite. Organism_taxid: 5833. Strain: it4. Gene: var. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.90Å R-factor: 0.223 R-free: 0.253

Authors:

K.Singh,A.G.Gittis,P.Nguyen,D.C.Gowda,L.H.Miller,D.N.Garboczi

Key ref:

K.Singh et al. (2008). Structure of the DBL3x domain of pregnancy-associated malaria protein VAR2CSA complexed with chondroitin sulfate A. Nat Struct Biol, 15, 932-938. PubMed id: 19172746 DOI: 10.1038/nsmb.1479

Date:

23-Mar-08 Release date: 02-Sep-08

Protein chain

Q6UDW7  (Q6UDW7_PLAFA) -  Erythrocyte membrane protein 1 from Plasmodium falciparum

Seq: 3064 a.a.

Struc: 317 a.a.

DOI no: 10.1038/nsmb.1479

Nat Struct Biol 15:932-938 (2008)

PubMed id: 19172746

Structure of the DBL3x domain of pregnancy-associated malaria protein VAR2CSA complexed with chondroitin sulfate A.

K.Singh, A.G.Gittis, P.Nguyen, D.C.Gowda, L.H.Miller, D.N.Garboczi.

ABSTRACT

Plasmodium falciparum-infected erythrocytes bind to chondroitin sulfate A (CSA) in the placenta via the VAR2CSA protein, a member of the P. falciparum erythrocyte membrane protein-1 family, leading to life-threatening malaria in pregnant women with severe effects on their fetuses and newborns. Here we describe the structure of the CSA binding DBL3x domain, a Duffy binding-like (DBL) domain of VAR2CSA. By forming a complex of DBL3x with CSA oligosaccharides and determining its structure, we have identified the CSA binding site to be a cluster of conserved positively charged residues on subdomain 2 and subdomain 3. Mutation or chemical modification of lysine residues at the site markedly diminished CSA binding to DBL3x. The location of the CSA binding site is an important step forward in the molecular understanding of pregnancy-associated malaria and offers a new target for vaccine development.

Selected figure(s)

Figure 2.
(a) View of the CSA electron density near helices H5 and H6. Residues with side chains within 5 Å of the density are identified. A sulfate group (sulfur, yellow; oxygen, red) has been placed in the density and is coordinated by the side chains of Lys1324, Arg1467 and Lys1504. The 2F[o] – F[c] map (dark blue) is contoured at 0.9 and the F[o] – F[c] map (cyan) is contoured at 2.5 . For clarity, Lys1327 is not shown. (b) Stereo view showing the CSA density, a sulfate group and the side chains of nearby residues. The DBL3x model without ligands was used to calculate phases for these maps.

Figure 4.
(a) Ribbon diagram of DBL3x overlayed on a semitransparent electrostatic potential surface. Side chains of lysines and arginines responsible for the positively charged region are shown in red. Subdomain 1 (yellow), subdomain 2 (blue) and subdomain 3 (red) are shown. For clarity, Lys1327 is not shown. (b) Positively charged areas (blue) are located on the sides of the binding area for the CSA oligosaccharide, shown in same orientation as in a. Lysines and arginines with side chains within 5 Å of the carbohydrate density are labeled (+, yellow). Below the CSA binding site is a region of negatively charged residues (red at arrow), which could prevent CSA from occupying the deeper portions of the 'valley' between subdomains 2 and 3. (c) View of a CSA hexasaccharide model^39 (PDB 1C4S) placed along the extra electron density seen in the crystals. The hexasaccharide shown here is approximately 30 Å in length and similar to the length of the observed electron density. Lys1327 is shown.

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: Nat Struct Biol (2008, 15, 932-938) copyright 2008.

Figures were selected by an automated process.