PDBsum entry 1qlp

Serine protease inhibitor

PDB id: 1qlp

Contents

Protein chain

372 a.a. *

Waters ×106

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Topography of a 2.0 a structure of alpha1-Antitrypsin reveals targets for rational drug design to prevent conformational disease.

Authors

P.R.Elliott, X.Y.Pei, T.R.Dafforn, D.A.Lomas.

Ref.

Protein Sci, 2000, 9, 1274-1281. [DOI no: 10.1110/ps.9.7.1274]

PubMed id

10933492

Abstract

Members of the serpin family of serine proteinase inhibitors play important roles in the inflammatory, coagulation, fibrinolytic, and complement cascades. An inherent part of their function is the ability to undergo a structural rearrangement, the stressed (S) to relaxed (R) transition, in which an extra strand is inserted into the central A beta-sheet. In order for this transition to take place, the A sheet has to be unusually flexible. Malfunctions in this flexibility can lead to aberrant protein linkage, serpin inactivation, and diseases as diverse as cirrhosis, thrombosis, angioedema, emphysema, and dementia. The development of agents that control this conformational rearrangement requires a high resolution structure of an active serpin. We present here the topology of the archetypal serpin alpha1-antitrypsin to 2 A resolution. This structure allows us to define five cavities that are potential targets for rational drug design to develop agents that will prevent conformational transitions and ameliorate the associated disease.

Secondary reference #1

Title

Wild-Type alpha 1-Antitrypsin is in the canonical inhibitory conformation.

Authors

P.R.Elliott, J.P.Abrahams, D.A.Lomas.

Ref.

J Mol Biol, 1998, 275, 419-425. [DOI no: 10.1006/jmbi.1997.1458]

PubMed id

9466920

Figure 1.
Figure 1. (a) The structure of wild-type α[1]-antitrypsin (red) is almost identical with that of α[1]-antitrypsin stabilized by the Phe51Leu mutation (black) apart from Ala347, Ala348 and Gly349 (P[12] to P[10]) of the reactive loop for which there is more clearly defined electron density than in Phe51Leu α[1]-antitrypsin. The position of the P[1] residue which docks with the substrate binding pocket of the cognate proteinase is shown. The reactive loop of α[1]-antitrypsin is stabilized by the salt bridge between P[5]glutamate and arginine residues 196, 223 and 281 ((b), left). The unfavourable proximity of the ring of arginine residues may contribute to the energy that drives the conformational transition that is characteristic of reactive loop cleavage ((b) right; [Loebermann et al 1984]). The structure was solved by molecular replacement using the coordinates of Phe51Leu α[1]-antitrypsin [Elliott et al 1996a] as a model and refined as detailed previously [Skinner et al 1997]. The coordinates and structure factors of the model have been deposited in the Brookhaven Data Bank as 2psi and r2psisf, respectively.

Figure 2.
Figure 2. Comparison of wild-type (yellow) and Phe51Leu-stabilized (white) α[1]-antitrypsin. The Phe51Leu mutation improves packing of 384Phe in the shutter domain of α[1]-antitrypsin. This has little effect on the A β-sheet that overlies this region but will hamper the movement of s2A and s3A to accept exogenous reactive loop peptides.

The above figures are reproduced from the cited reference with permission from Elsevier