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Crystal structures of the FXIa catalytic domain in complex with ecotin mutants reveal substrate-like interactions.

Jin L, Pandey P, Babine RE, Gorga JC, Seidl KJ, Gelfand E, Weaver DT, Abdel-Meguid SS, Strickler JE
J Biol Chem 280 4704-12 (2005)
Related entries: 1xx9, 1xxf

Cited: 30 times
EuropePMC logo PMID: 15545266

Abstract

Thrombosis can lead to life-threatening conditions such as acute myocardial infarction, pulmonary embolism, and stroke. Although commonly used anti-coagulant drugs, such as low molecular weight heparin and warfarin, are effective, they carry a significant risk of inducing severe bleeding complications, and there is a need for safer drugs. Activated Factor XI (FXIa) is a key enzyme in the amplification phase of the coagulation cascade. Anti-human FXI antibody significantly reduces thrombus growth in a baboon thrombosis model without bleeding problems (Gruber, A., and Hanson, S. R. (2003) Blood 102, 953-955). Therefore, FXIa is a potential target for anti-thrombosis therapy. To determine the structure of FXIa, we derived a recombinant catalytic domain of FXI, consisting of residues 370-607 (rhFXI370-607). Here we report the first crystal structure of rhFXI370-607 in complex with a substitution mutant of ecotin, a panserine protease protein inhibitor secreted by Escherichia coli, to 2.2 A resolution. The presence of ecotin not only assisted in the crystallization of the enzyme but also revealed unique structural features in the active site of FXIa. Subsequently, the sequence from P5 to P2' in ecotin was mutated to the FXIa substrate sequence, and the structures of the rhFXI370-607-ecotin mutant complexes were determined. These structures provide us with an understanding of substrate binding interactions of FXIa, the structural information essential for the structure-based design of FXIa-selective inhibitors.

Articles - 1xxd mentioned but not cited (3)

  1. Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design. Fjellström O, Akkaya S, Beisel HG, Eriksson PO, Erixon K, Gustafsson D, Jurva U, Kang D, Karis D, Knecht W, Nerme V, Nilsson I, Olsson T, Redzic A, Roth R, Sandmark J, Tigerström A, Öster L. PLoS One 10 e0113705 (2015)
  2. Functional role of residue 193 (chymotrypsin numbering) in serine proteases: influence of side chain length and beta-branching on the catalytic activity of blood coagulation factor XIa. Schmidt AE, Sun MF, Ogawa T, Bajaj SP, Gailani D. Biochemistry 47 1326-1335 (2008)
  3. Prediction of Suicide-Related Events by Analyzing Electronic Medical Records from PTSD Patients with Bipolar Disorder. Fan P, Guo X, Qi X, Matharu M, Patel R, Sakolsky D, Kirisci L, Silverstein JC, Wang L. Brain Sci 10 E784 (2020)


Reviews citing this publication (3)

  1. Structure and function of factor XI. Emsley J, McEwan PA, Gailani D. Blood 115 2569-2577 (2010)
  2. Prokaryote-derived protein inhibitors of peptidases: A sketchy occurrence and mostly unknown function. Kantyka T, Rawlings ND, Potempa J. Biochimie 92 1644-1656 (2010)
  3. Recent advances in the discovery and development of factor XI/XIa inhibitors. Al-Horani RA, Afosah DK. Med Res Rev 38 1974-2023 (2018)

Articles citing this publication (24)

  1. Expression, crystallization, and three-dimensional structure of the catalytic domain of human plasma kallikrein. Tang J, Yu CL, Williams SR, Springman E, Jeffery D, Sprengeler PA, Estevez A, Sampang J, Shrader W, Spencer J, Young W, McGrath M, Katz BA. J Biol Chem 280 41077-41089 (2005)
  2. Factor XI deficiency database: an interactive web database of mutations, phenotypes, and structural analysis tools. Saunders RE, O'Connell NM, Lee CA, Perry DJ, Perkins SJ. Hum Mutat 26 192-198 (2005)
  3. Characterization of a heparin-binding site on the catalytic domain of factor XIa: mechanism of heparin acceleration of factor XIa inhibition by the serpins antithrombin and C1-inhibitor. Yang L, Sun MF, Gailani D, Rezaie AR. Biochemistry 48 1517-1524 (2009)
  4. Synthesis, SAR exploration, and X-ray crystal structures of factor XIa inhibitors containing an alpha-ketothiazole arginine. Deng H, Bannister TD, Jin L, Babine RE, Quinn J, Nagafuji P, Celatka CA, Lin J, Lazarova TI, Rynkiewicz MJ, Bibbins F, Pandey P, Gorga J, Meyers HV, Abdel-Meguid SS, Strickler JE. Bioorg Med Chem Lett 16 3049-3054 (2006)
  5. Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site. Karuturi R, Al-Horani RA, Mehta SC, Gailani D, Desai UR. J Med Chem 56 2415-2428 (2013)
  6. Coagulation factor XII protease domain crystal structure. Pathak M, Wilmann P, Awford J, Li C, Hamad BK, Fischer PM, Dreveny I, Dekker LV, Emsley J. J Thromb Haemost 13 580-591 (2015)
  7. Solution structure of the A4 domain of factor XI sheds light on the mechanism of zymogen activation. Samuel D, Cheng H, Riley PW, Canutescu AA, Nagaswami C, Weisel JW, Bu Z, Walsh PN, Roder H. Proc Natl Acad Sci U S A 104 15693-15698 (2007)
  8. Synthesis and in vitro biological evaluation of aryl boronic acids as potential inhibitors of factor XIa. Lazarova TI, Jin L, Rynkiewicz M, Gorga JC, Bibbins F, Meyers HV, Babine R, Strickler J. Bioorg Med Chem Lett 16 5022-5027 (2006)
  9. Contribution of exosite occupancy by heparin to the regulation of coagulation proteases by antithrombin. Yang L, Manithody C, Qureshi SH, Rezaie AR. Thromb Haemost 103 277-283 (2010)
  10. Membrane-dependent interaction of factor Xa and prothrombin with factor Va in the prothrombinase complex. Qureshi SH, Yang L, Manithody C, Rezaie AR. Biochemistry 48 5034-5041 (2009)
  11. Structures of human plasma β-factor XIIa cocrystallized with potent inhibitors. Dementiev A, Silva A, Yee C, Li Z, Flavin MT, Sham H, Partridge JR. Blood Adv 2 549-558 (2018)
  12. Data mining PubChem using a support vector machine with the Signature molecular descriptor: classification of factor XIa inhibitors. Weis DC, Visco DP, Faulon JL. J Mol Graph Model 27 466-475 (2008)
  13. The serine protease domain of MASP-3: enzymatic properties and crystal structure in complex with ecotin. Gaboriaud C, Gupta RK, Martin L, Lacroix M, Serre L, Teillet F, Arlaud GJ, Rossi V, Thielens NM. PLoS One 8 e67962 (2013)
  14. Network approach for capturing ligand-induced subtle global changes in protein structures. Sukhwal A, Bhattacharyya M, Vishveshwara S. Acta Crystallogr D Biol Crystallogr 67 429-439 (2011)
  15. Structural modeling and analysis of the SARS-CoV-2 cell entry inhibitor camostat bound to the trypsin-like protease TMPRSS2. Escalante DE, Ferguson DM. Med Chem Res 30 399-409 (2021)
  16. Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation. Hamad BK, Pathak M, Manna R, Fischer PM, Emsley J, Dekker LV. J Thromb Haemost 15 1818-1828 (2017)
  17. Productive recognition of factor IX by factor XIa exosites requires disulfide linkage between heavy and light chains of factor XIa. Marcinkiewicz MM, Sinha D, Walsh PN. J Biol Chem 287 6187-6195 (2012)
  18. A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency. Bozzao C, Rimoldi V, Asselta R, Landau M, Ghiotto R, Tenchini ML, De Cristofaro R, Castaman G, Duga S. FEBS J 274 6128-6138 (2007)
  19. Analysis of an engineered plasma kallikrein inhibitor and its effect on contact activation. Stoop AA, Joshi RV, Eggers CT, Craik CS. Biol Chem 391 425-433 (2010)
  20. Identification of an alpha-1 antitrypsin variant with enhanced specificity for factor XIa by phage display, bacterial expression, and combinatorial mutagenesis. Bhakta V, Hamada M, Nouanesengsy A, Lapierre J, Perruzza DL, Sheffield WP. Sci Rep 11 5565 (2021)
  21. Structural Basis for Activity and Specificity of an Anticoagulant Anti-FXIa Monoclonal Antibody and a Reversal Agent. Ely LK, Lolicato M, David T, Lowe K, Kim YC, Samuel D, Bessette P, Garcia JL, Mikita T, Minor DL, Coughlin SR. Structure 26 187-198.e4 (2018)
  22. The role of factor XIa (FXIa) catalytic domain exosite residues in substrate catalysis and inhibition by the Kunitz protease inhibitor domain of protease nexin 2. Su YC, Miller TN, Navaneetham D, Schoonmaker RT, Sinha D, Walsh PN. J Biol Chem 286 31904-31914 (2011)
  23. A receptor dependent-4D QSAR approach to predict the activity of mutated enzymes. Kumar RP, Kulkarni N. Sci Rep 7 6273 (2017)
  24. [A family with hereditary FⅪ deficiency caused by compound heterozygous mutation]. Zheng XY, Jin YH, Xu YY, Yang LL, Zhu LQ, Wang HH, Jiang ST, Wang MS. Zhonghua Xue Ye Xue Za Zhi 42 687-689 (2021)


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