ArticleProtein science : a publication of the Protein Society1992
Direct observation by X-ray analysis of the tetrahedral "intermediate" of aspartic proteinases.
Article in Protein science : a publication of the Protein Society, 1992. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 121 citations in OpenAlex.
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- Discovery of new Schistosoma mansoni aspartyl protease inhibitors by structure-based virtual screening.Memorias do Instituto Oswaldo Cruz · 2023Article
- Elucidating the multiple roles of hydration for accurate protein-ligand binding prediction via deep learning.Communications chemistry · 2020Article
- Crystallization of nepenthesin I using a low-pH crystallization screen.Acta crystallographica. Section F, Structural biology communications · 2016Article
- The structure of endothiapepsin complexed with a Phe-Tyr reduced-bond inhibitor at 1.35 Å resolution.Acta crystallographica. Section F, Structural biology communications · 2014Article
- Aspartic peptidases of human pathogenic trypanosomatids: perspectives and trends for chemotherapy.Current medicinal chemistry · 2013Review
- A high performance cloud-based protein-ligand docking prediction algorithm.BioMed research international · 2013Article
- Capturing the reaction pathway in near-atomic-resolution crystal structures of HIV-1 protease.Biochemistry · 2012Article
- Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of piperidine and piperazine aryl ureas.Journal of medicinal chemistry · 2011Article
- Statistical coupling analysis of aspartic proteinases based on crystal structures of the Trichoderma reesei enzyme and its complex with pepstatin A.Journal of molecular biology · 2008Article
- The catalytic mechanism of an aspartic proteinase explored with neutron and X-ray diffraction.Journal of the American Chemical Society · 2008Article
- Preliminary neutron and ultrahigh-resolution X-ray diffraction studies of the aspartic proteinase endothiapepsin cocrystallized with a gem-diol inhibitor.Acta crystallographica. Section F, Structural biology and crystallization communications · 2007Article
- X-ray, neutron and NMR studies of the catalytic mechanism of aspartic proteinases.European biophysics journal : EBJ · 2006Article
- Assigning the protonation states of the key aspartates in β-Secretase using QM/MM X-ray structure refinement.Journal of chemical theory and computation · 2006Article
- Atomic resolution analysis of the catalytic site of an aspartic proteinase and an unexpected mode of binding by short peptides.Protein science : a publication of the Protein Society · 2003Article
- Analysis of crystal structures of aspartic proteinases: on the role of amino acid residues adjacent to the catalytic site of pepsin-like enzymes.Protein science : a publication of the Protein Society · 2001Article
- Identification of active sites in amidase: evolutionary relationship between amide bond- and peptide bond-cleaving enzymes.Proceedings of the National Academy of Sciences of the United States of America · 1997Article
- Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes.Journal of computer-aided molecular design · 1997Article
- Mechanism of action of aspartic proteinases: application of transition-state analogue theory.Journal of computer-aided molecular design · 1996Article
- Aspartic proteinases: Fourier transform infrared spectroscopic studies of a model of the active side.Biophysical journal · 1996Article
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8 authors at 2 institutions in 2 countries.
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Abstract
We report the X-ray analysis at 2.0 A resolution for crystals of the aspartic proteinase endothiapepsin (EC 3.4.23.6) complexed with a potent difluorostatone-containing tripeptide renin inhibitor (CP-81,282). The scissile bond surrogate, an electrophilic ketone, is hydrated in the complex. The pro-(R) (statine-like) hydroxyl of the tetrahedral carbonyl hydrate is hydrogen-bonded to both active-site aspartates 32 and 215 in the position occupied by a water in the native enzyme. The second hydroxyl oxygen of the hydrate is hydrogen-bonded only to the outer oxygen of Asp 32. These experimental data provide a basis for a model of the tetrahedral intermediate in aspartic proteinase-mediated cleavage of the amide bond. This indicates a mechanism in which Asp 32 is the proton donor and Asp 215 carboxylate polarizes a bound water for nucleophilic attack. The mechanism involves a carboxylate (Asp 32) that is stabilized by extensive hydrogen bonding, rather than an oxyanion derivative of the peptide as in serine proteinase catalysis.
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