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Crystal structure of the complex of plasminogen activator inhibitor 2 with a peptide mimicking the reactive center loop.

Jankova L, Harrop SJ, Saunders DN, Andrews JL, Bertram KC, Gould AR, Baker MS, Curmi PM
J Biol Chem 276 43374-82 (2001)
Cited: 11 times
EuropePMC logo PMID: 11546761

Abstract

The structure of the serpin, plasminogen activator inhibitor type-2 (PAI-2), in a complex with a peptide mimicking its reactive center loop (RCL) has been determined at 1.6-A resolution. The structure shows the relaxed state serpin structure with a prominent six-stranded beta-sheet. Clear electron density is seen for all residues in the peptide. The P1 residue of the peptide binds to a well defined pocket at the base of PAI-2 that may be important in determining the specificity of protease inhibition. The stressed-to-relaxed state (S --> R) transition in PAI-2 can be modeled as the relative motion between a quasirigid core domain and a smaller segment comprising helix hF and beta-strands s1A, s2A, and s3A. A comparison of the Ramachandran plots of the stressed and relaxed state PAI-2 structures reveals the location of several hinge regions connecting these two domains. The hinge regions cluster in three locations on the structure, ensuring a cooperative S --> R transition. We hypothesize that the hinge formed by the conserved Gly(206) on beta-strand s3A in the breach region of PAI-2 effects the S --> R transition by altering its backbone torsion angles. This torsional change is due to the binding of the P14 threonine of the RCL to the open breach region of PAI-2.

Articles - 1jrr mentioned but not cited (2)

  1. A structural basis for differential cell signalling by PAI-1 and PAI-2 in breast cancer cells. Croucher DR, Saunders DN, Stillfried GE, Ranson M. Biochem. J. 408 203-210 (2007)
  2. Screening of Potential Anti-Thrombotic Ingredients from Salvia miltiorrhiza in Zebrafish and by Molecular Docking. Tang H, Qin N, Rao C, Zhu J, Wang H, Hu G. Molecules 26 6807 (2021)


Reviews citing this publication (2)

  1. Conformational pathology of the serpins: themes, variations, and therapeutic strategies. Gooptu B, Lomas DA. Annu. Rev. Biochem. 78 147-176 (2009)
  2. Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Croucher DR, Saunders DN, Lobov S, Ranson M. Nat. Rev. Cancer 8 535-545 (2008)

Articles citing this publication (7)

  1. A redox-sensitive loop regulates plasminogen activator inhibitor type 2 (PAI-2) polymerization. Wilczynska M, Lobov S, Ohlsson PI, Ny T. EMBO J. 22 1753-1761 (2003)
  2. Kinetic analysis of plasminogen activator inhibitor type-2: urokinase complex formation and subsequent internalisation by carcinoma cell lines. Al-Ejeh F, Croucher D, Ranson M. Exp. Cell Res. 297 259-271 (2004)
  3. Structural differences between active forms of plasminogen activator inhibitor type 1 revealed by conformationally sensitive ligands. Li SH, Gorlatova NV, Lawrence DA, Schwartz BS. J. Biol. Chem. 283 18147-18157 (2008)
  4. Plasminogen activator inhibitor-2 is expressed in different types of congenital ichthyosis: in vivo evidence for its cross-linking into the cornified cell envelope by transglutaminase-1. Oji V, Oji ME, Adamini N, Walker T, Aufenvenne K, Raghunath M, Traupe H. Br. J. Dermatol. 154 860-867 (2006)
  5. The CD-loop of PAI-2 (SERPINB2) is redundant in the targeting, inhibition and clearance of cell surface uPA activity. Cochran BJ, Gunawardhana LP, Vine KL, Lee JA, Lobov S, Ranson M. BMC Biotechnol. 9 43 (2009)
  6. Plasminogen activator inhibitor-2 is highly tolerant to P8 residue substitution--implications for serpin mechanistic model and prediction of nsSNP activities. Di Giusto DA, Sutherland AP, Jankova L, Harrop SJ, Curmi PM, King GC. J. Mol. Biol. 353 1069-1080 (2005)
  7. Peptides based on the reactive center loop of Manduca sexta serpin-3 block its protease inhibitory function. Li M, Takahashi D, Kanost MR. Sci Rep 10 11497 (2020)


Related citations provided by authors (1)

  1. INTERACTION BETWEEN THE P14 RESIDUE AND STRAND 2 OF BETA-SHEET B IS CRITICAL FOR REACTIVE CENTER LOOP INSERTION IN PAI-2. SAUNDERS DN, GOULD AR, RANSON M, JANKOVA L, HARROP SJ, G CURMI PM, BAKER MS To be published -

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