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Five atomic resolution structures of endothiapepsin inhibitor complexes: implications for the aspartic proteinase mechanism.

Coates L, Erskine PT, Crump MP, Wood SP, Cooper JB
J Mol Biol 318 1405-15 (2002)
Related entries: 1gvt, 1gvu, 1gvv, 1gvw

Cited: 17 times
EuropePMC logo PMID: 12083527

Abstract

Endothiapepsin is derived from the fungus Endothia parasitica and is a member of the aspartic proteinase class of enzymes. This class of enzyme is comprised of two structurally similar lobes, each lobe contributing an aspartic acid residue to form a catalytic dyad that acts to cleave the substrate peptide bond. The three-dimensional structures of endothiapepsin bound to five transition state analogue inhibitors (H189, H256, CP-80,794, PD-129,541 and PD-130,328) have been solved at atomic resolution allowing full anisotropic modelling of each complex. The active sites of the five structures have been studied with a view to studying the catalytic mechanism of the aspartic proteinases by locating the active site protons by carboxyl bond length differences and electron density analysis. In the CP-80,794 structure there is excellent electron density for the hydrogen on the inhibitory statine hydroxyl group which forms a hydrogen bond with the inner oxygen of Asp32. The location of this proton has implications for the catalytic mechanism of the aspartic proteinases as it is consistent with the proposed mechanism in which Asp32 is the negatively charged aspartate. A number of short hydrogen bonds (approximately 2.6 A) with ESD values of around 0.01 A that may have a role in catalysis have been identified within the active site of each structure; the lengths of these bonds have been confirmed using NMR techniques. The possibility and implications of low barrier hydrogen bonds in the active site are considered.

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  1. Low barrier hydrogen bonds in protein structure and function. Kemp MT, Lewandowski EM, Chen Y. Biochim Biophys Acta Proteins Proteom 1869 140557 (2021)

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  1. Cysteine pKa depression by a protonated glutamic acid in human DJ-1. Witt AC, Lakshminarasimhan M, Remington BC, Hasim S, Pozharski E, Wilson MA. Biochemistry 47 7430-7440 (2008)
  2. The catalytic mechanism of an aspartic proteinase explored with neutron and X-ray diffraction. Coates L, Tuan HF, Tomanicek S, Kovalevsky A, Mustyakimov M, Erskine P, Cooper J. J Am Chem Soc 130 7235-7237 (2008)
  3. X-ray, neutron and NMR studies of the catalytic mechanism of aspartic proteinases. Coates L, Erskine PT, Mall S, Gill R, Wood SP, Myles DA, Cooper JB. Eur Biophys J 35 559-566 (2006)
  4. An in silico approach for identification of novel inhibitors as potential therapeutics targeting COVID-19 main protease. Havranek B, Islam SM. J Biomol Struct Dyn 39 4304-4315 (2021)
  5. Short Carboxylic Acid-Carboxylate Hydrogen Bonds Can Have Fully Localized Protons. Lin J, Pozharski E, Wilson MA. Biochemistry 56 391-402 (2017)
  6. Atomic resolution analysis of the catalytic site of an aspartic proteinase and an unexpected mode of binding by short peptides. Erskine PT, Coates L, Mall S, Gill RS, Wood SP, Myles DA, Cooper JB. Protein Sci 12 1741-1749 (2003)
  7. Crystal structure of aspartic proteinase from Irpex lacteus in complex with inhibitor pepstatin. Fujimoto Z, Fujii Y, Kaneko S, Kobayashi H, Mizuno H. J Mol Biol 341 1227-1235 (2004)
  8. Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies. Sabbah DA, Zhong HA. J Mol Graph Model 68 206-215 (2016)
  9. Crystal structures of Aspergillus oryzae aspartic proteinase and its complex with an inhibitor pepstatin at 1.9A resolution. Kamitori S, Ohtaki A, Ino H, Takeuchi M. J Mol Biol 326 1503-1511 (2003)
  10. Atomic resolution crystal structure of Sapp2p, a secreted aspartic protease from Candida parapsilosis. Dostál J, Pecina A, Hrušková-Heidingsfeldová O, Marečková L, Pichová I, Řezáčová P, Lepšík M, Brynda J. Acta Crystallogr D Biol Crystallogr 71 2494-2504 (2015)
  11. Deciphering the mechanism of potent peptidomimetic inhibitors targeting plasmepsins - biochemical and structural insights. Mishra V, Rathore I, Arekar A, Sthanam LK, Xiao H, Kiso Y, Sen S, Patankar S, Gustchina A, Hidaka K, Wlodawer A, Yada RY, Bhaumik P. FEBS J 285 3077-3096 (2018)
  12. Prediction and evaluation of deleterious and disease causing non-synonymous SNPs (nsSNPs) in human NF2 gene responsible for neurofibromatosis type 2 (NF2). Havranek B, Islam SM. J Biomol Struct Dyn 39 7044-7055 (2021)
  13. Synthesis of α-carboxyphosphinopeptides derived from norleucine. Pícha J, Buděšínský M, Fiedler P, Sanda M, Jiráček J. Amino Acids 39 1265-1280 (2010)
  14. Discovery of new Schistosoma mansoni aspartyl protease inhibitors by structure-based virtual screening. Gomes BF, Senger MR, Moreira-Filho JT, Vasconcellos Junior FJ, Dantas RF, Owens R, Andrade CH, Neves BJ, Silva-Junior FP. Mem Inst Oswaldo Cruz 118 e230031 (2023)
  15. Preliminary neutron and ultrahigh-resolution X-ray diffraction studies of the aspartic proteinase endothiapepsin cocrystallized with a gem-diol inhibitor. Tuan HF, Erskine P, Langan P, Cooper J, Coates L. Acta Crystallogr Sect F Struct Biol Cryst Commun 63 1080-1083 (2007)


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