PDBsum entry 2erq

Toxin

PDB id: 2erq

Contents

Protein chains

424 a.a. *

Ligands

NAG-NAG

NAG

Metals

_CA ×4

_ZN ×2

Waters ×165

* Residue conservation analysis

PDB id:

2erq

Name:

Toxin

Title:

Crystal structure of vascular apoptosis-inducing protein-1(tetragonal crystal form)

Structure:

Vascular apoptosis-inducing protein 1. Chain: a, b. Fragment: residues 184-610. Synonym: vap-1

Source:

Crotalus atrox. Western diamondback rattlesnake. Organism_taxid: 8730. Secretion: venom

Biol. unit:

Dimer (from PQS)

Resolution:

2.50Å R-factor: 0.229 R-free: 0.269

Authors:

S.Takeda,T.Igarashi,S.Araki

Key ref:

S.Takeda et al. (2006). Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C-shaped scaffold. EMBO J, 25, 2388-2396. PubMed id: 16688218 DOI: 10.1038/sj.emboj.7601131

Date:

25-Oct-05 Release date: 20-Jun-06

Protein chains

Q9DGB9  (VM3V1_CROAT) -  Zinc metalloproteinase-disintegrin-like VAP1 from Crotalus atrox

Seq: 610 a.a.

Struc: 424 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.24.- - ?????

DOI no: 10.1038/sj.emboj.7601131

EMBO J 25:2388-2396 (2006)

PubMed id: 16688218

Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C-shaped scaffold.

S.Takeda, T.Igarashi, H.Mori, S.Araki.

ABSTRACT

ADAMs (a disintegrin and metalloproteinase) are sheddases possessing extracellular metalloproteinase/disintegrin/cysteine-rich (MDC) domains. ADAMs uniquely display both proteolytic and adhesive activities on the cell surface, however, most of their physiological targets and adhesion mechanisms remain unclear. Here for the first time, we reveal the ADAMs' MDC architecture and a potential target-binding site by solving crystal structures of VAP1, a snake venom homolog of mammalian ADAMs. The D-domain protrudes from the M-domain opposing the catalytic site and constituting a C-shaped arm with cores of Ca2+ ions. The disintegrin-loop, supposed to interact with integrins, is packed by the C-domain and inaccessible for protein binding. Instead, the hyper-variable region (HVR) in the C-domain, which has a novel fold stabilized by the strictly conserved disulfide bridges, constitutes a potential protein-protein adhesive interface. The HVR is located at the distal end of the arm and faces toward the catalytic site. The C-shaped structure implies interplay between the ADAMs' proteolytic and adhesive domains and suggests a molecular mechanism for ADAMs' target recognition for shedding.

Selected figure(s)

Figure 1.
Figure 1 MDC architecture. (A) VAP1 dimer viewed from the NCS axis. The H0-helix, M-domain, linker, D[s]-, D[a]-, C[w]-, and C[h]-domains and HVRs belonging to the one monomer are shown in red, yellow, gray, cyan, pink, gray, green and blue, respectively. The disulfide-linked counterpart is shown in gray. Zinc and calcium ions are represented as red and black spheres, respectively. The NAG (N-acetyl-glucosamine, in orange) moieties linked to Asn218, the calcium-mimetic Lys202 and the bound inhibitor GM6001 (GM, in green) are in ball-stick representations. (B) Stereo view of VAP1 monomer from the direction nearly perpendicular to (A). The helix numbers are labelled. (C) Superposition of the M-domains of ADAM33 (blue) and VAP1 (yellow). The calcium ion bound to site I and the zinc ion in ADAM33 are represented by black and red spheres, respectively. The disulfide bridges are indicated in black and blue letters for VAP1 and ADAM33, respectively. The QDHSK sequence for the dimer interface in VAP1 (residues 320–324) is in red. (D) Comparison of the calcium-binding site I structures of ADAM33 (blue) and VAP1 (yellow) in stereo. The residues in ADAM33 and in VAP1 are labelled in blue and black, respectively. A calcium ion and a water molecule bound to ADAM33 are represented as green and red spheres, respectively. The ammonium group of Lys202 in VAP1 occupies the position of the calcium ion in ADAM33. In ADAM33 (Orth et al, 2004), side-chain oxygen atoms of Glu213, Asp296 and Asn407, the carbonyl oxygen of Cys404 and a water molecule form the corners of a pentagonal bipyramid and ligand to the calcium ion.

Figure 4.
Figure 4 C-domain architecture and HVR. (A) The C-domain architecture in stereo. The C[w]- and C[h]-domains are in gray and light green, respectively. The disulfide bridges and the residues forming the hydrophobic ridges are indicated. The HVR and its NCS counterpart are shown in red and blue, respectively. The variable loop (residues 539–549), flanked by two adjacent cysteine residues, is in green. (B) Crystal packing in the orthorhombic crystal. The crystallographically equivalent molecules (HVRs) are in cyan (blue) and pink (red), respectively. The arrows indicate the directions of the HVR chains. Zinc and calcium ions are represented as red and black spheres, respectively. (C) Interactions between the HVRs (cyan and pink) in stereo. The molecular surface of the cyan molecule is shown with the electrochemical surface potential (red to blue). The residues constituting the hydrophobic ridges are in yellow. The residues are labelled in blue and red for cyan and pink, respectively. (D) Water-mediated hydrogen-bond network in the HVR. The HVR residues are in pink and cyan; non-HVR residues in the pink molecule are in gray.

The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO J (2006, 25, 2388-2396) copyright 2006.

Figures were selected by an automated process.