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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 1741-9 (2003)
Cited: 14 times
EuropePMC logo PMID: 12876323

Abstract

The X-ray structures of native endothiapepsin and a complex with a hydroxyethylene transition state analog inhibitor (H261) have been determined at atomic resolution. Unrestrained refinement of the carboxyl groups of the enzyme by using the atomic resolution data indicates that both catalytic aspartates in the native enzyme share a single negative charge equally; that is, in the crystal, one half of the active sites have Asp 32 ionized and the other half have Asp 215 ionized. The electron density map of the native enzyme refined at 0.9 A resolution demonstrates that there is a short peptide (probably Ser-Thr) bound noncovalently in the active site cleft. The N-terminal nitrogen of the dipeptide interacts with the aspartate diad of the enzyme by hydrogen bonds involving the carboxyl of Asp 215 and the catalytic water molecule. This is consistent with classical findings that the aspartic proteinases can be inhibited weakly by short peptides and that these enzymes can catalyze transpeptidation reactions. The dipeptide may originate from autolysis of the N-terminal Ser-Thr sequence of the enzyme during crystallization.

Articles - 1oew mentioned but not cited (5)

  1. 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)
  2. Statistical coupling analysis of aspartic proteinases based on crystal structures of the Trichoderma reesei enzyme and its complex with pepstatin A. Nascimento AS, Krauchenco S, Golubev AM, Gustchina A, Wlodawer A, Polikarpov I. J Mol Biol 382 763-778 (2008)
  3. Using neural networks and evolutionary information in decoy discrimination for protein tertiary structure prediction. Tan CW, Jones DT. BMC Bioinformatics 9 94 (2008)
  4. A novel secondary structure based on fused five-membered rings motif. Dhar J, Kishore R, Chakrabarti P. Sci Rep 6 31483 (2016)
  5. The oxygen-oxygen distance of water in crystallographic data sets. Palese LL. Data Brief 28 105076 (2020)


Reviews citing this publication (1)

  1. Structural studies of vacuolar plasmepsins. Bhaumik P, Gustchina A, Wlodawer A. Biochim Biophys Acta 1824 207-223 (2012)

Articles citing this publication (8)

  1. The backrub motion: how protein backbone shrugs when a sidechain dances. Davis IW, Arendall WB, Richardson DC, Richardson JS. Structure 14 265-274 (2006)
  2. Crystal structures of the histo-aspartic protease (HAP) from Plasmodium falciparum. Bhaumik P, Xiao H, Parr CL, Kiso Y, Gustchina A, Yada RY, Wlodawer A. J Mol Biol 388 520-540 (2009)
  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. Room-temperature neutron and X-ray data collection of 3CL Mpro from SARS-CoV-2. Kneller DW, Phillips G, Kovalevsky A, Coates L. Acta Crystallogr F Struct Biol Commun 76 483-487 (2020)
  5. Experimental and computational active site mapping as a starting point to fragment-based lead discovery. Behnen J, Köster H, Neudert G, Craan T, Heine A, Klebe G. ChemMedChem 7 248-261 (2012)
  6. New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM. Fadel F, Zhao Y, Cachau R, Cousido-Siah A, Ruiz FX, Harlos K, Howard E, Mitschler A, Podjarny A. Acta Crystallogr D Biol Crystallogr 71 1455-1470 (2015)
  7. Structural insights into the activation and inhibition of histo-aspartic protease from Plasmodium falciparum. Bhaumik P, Xiao H, Hidaka K, Gustchina A, Kiso Y, Yada RY, Wlodawer A. Biochemistry 50 8862-8879 (2011)
  8. Encapsulation of Aspartic Protease in Nonlamellar Lipid Liquid Crystalline Phases. Valldeperas M, Talaikis M, Dhayal SK, Velička M, Barauskas J, Niaura G, Nylander T. Biophys J 117 829-843 (2019)


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