PDBsum entry 3cwl

Protease inhibitor

PDB id: 3cwl

Contents

Protein chain

372 a.a. *

Metals

_CL

Waters ×86

* Residue conservation analysis

PDB id:

3cwl

Name:

Protease inhibitor

Title:

Crystal structure of alpha-1-antitrypsin, crystal form b

Structure:

Alpha-1-antitrypsin. Chain: a. Synonym: alpha-1 protease inhibitor, alpha-1- antiproteinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: serpina1, aat, pi. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.44Å R-factor: 0.218 R-free: 0.264

Authors:

C.J.Morton,G.Hansen,S.C.Feil,J.J.Adams,M.W.Parker

Key ref:

M.C.Pearce et al. (2008). Preventing serpin aggregation: The molecular mechanism of citrate action upon antitrypsin unfolding. Protein Sci, 17, 2127-2133. PubMed id: 18780818 DOI: 10.1110/ps.037234.108

Date:

22-Apr-08 Release date: 23-Sep-08

Protein chain

P01009  (A1AT_HUMAN) -  Alpha-1-antitrypsin from Homo sapiens

Seq: 418 a.a.

Struc: 372 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1110/ps.037234.108

Protein Sci 17:2127-2133 (2008)

PubMed id: 18780818

Preventing serpin aggregation: The molecular mechanism of citrate action upon antitrypsin unfolding.

M.C.Pearce, C.J.Morton, S.C.Feil, G.Hansen, J.J.Adams, M.W.Parker, S.P.Bottomley.

ABSTRACT

The aggregation of antitrypsin into polymers is one of the causes of neonatal hepatitis, cirrhosis, and emphysema. A similar reaction resulting in disease can occur in other human serpins, and collectively they are known as the serpinopathies. One possible therapeutic strategy involves inhibiting the conformational changes involved in antitrypsin aggregation. The citrate ion has previously been shown to prevent antitrypsin aggregation and maintain the protein in an active conformation; its mechanism of action, however, is unknown. Here we demonstrate that the citrate ion prevents the initial misfolding of the native state to a polymerogenic intermediate in a concentration-dependent manner. Furthermore, we have solved the crystal structure of citrate bound to antitrypsin and show that a single citrate molecule binds in a pocket between the A and B beta-sheets, a region known to be important in maintaining antitrypsin stability.

Selected figure(s)

Figure 3.
Diagrammatic representation of the three-dimensional structure of the AAT --citrate complex. The protein is shown in ribbon style, with sheet A in blue, sheet B in red, sheet C in yellow, the reactive center loop in green, and the citrate ion is shown as cyan-colored spheres.

Figure 4.
Analysis of the citrate-binding pocket. Stereoscopic figure of residues contributing to the citrate-binding pocket in (A) crystal form A, (B) crystal form B, and (C) the citrate complex. In all three, the protein is shown as sticks colored by atom type (carbon: green, oxygen: red, nitrogen: blue, sulfur: yellow), with water molecules shown as red spheres. In crystal form B, the chloride ion is shown as an orange sphere (B) while in the citrate complex (B) the citrate is shown as sticks colored by atom type, except that the carbon atoms are in cyan. Comparison of the three sites shows that minimal rearrangement of the site has occurred to adapt to citrate binding.

The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (2008, 17, 2127-2133) copyright 2008.

Figures were selected by an automated process.