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An allosteric site enables fine-tuning of cathepsin K by diverse effectors.

Novinec M, Rebernik M, Lenarčič B
FEBS Lett 590 4507-4518 (2016)
Cited: 8 times
EuropePMC logo PMID: 27859061

Abstract

The cysteine peptidase cathepsin K is a potent collagenolytic enzyme and a promising target for the treatment of osteoporosis. Here, we characterize its allosteric fine-tuning via a recently identified allosteric site. We show that compound NSC94914 binds this site and acts as a specific partial inhibitor of the collagenolytic activity of cathepsin K. We link the functional differences between NSC94914 and known effectors (compound NSC11345 and glycosaminoglycans) to their different modes of interaction with the site. We characterize the allosteric site by site-directed mutagenesis and show that it is involved in specific regulation of the collagenolytic activity of cathepsin K.

Articles - 5ja7 mentioned but not cited (2)

  1. Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases. Novinec M. PLoS One 12 e0182387 (2017)
  2. Dissecting a novel allosteric mechanism of cruzain: A computer-aided approach. Hernández Alvarez L, Barreto Gomes DE, Hernández González JE, Pascutti PG. PLoS One 14 e0211227 (2019)


Reviews citing this publication (1)

  1. Recent applications of computational methods to allosteric drug discovery. Govindaraj RG, Thangapandian S, Schauperl M, Denny RA, Diller DJ. Front Mol Biosci 9 1070328 (2022)

Articles citing this publication (5)

  1. N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) inhibits the angiogenic activity of heparin-binding growth factors. Nawaz IM, Chiodelli P, Rezzola S, Paganini G, Corsini M, Lodola A, Di Ianni A, Mor M, Presta M. Angiogenesis 21 47-59 (2018)
  2. Allosteric Site Inhibitor Disrupting Auto-Processing of Malarial Cysteine Proteases. Pant A, Kumar R, Wani NA, Verma S, Sharma R, Pande V, Saxena AK, Dixit R, Rai R, Pandey KC. Sci Rep 8 16193 (2018)
  3. Identification of Plasmodium dipeptidyl aminopeptidase allosteric inhibitors by high throughput screening. Sanchez MI, de Vries LE, Lehmann C, Lee JT, Ang KK, Wilson C, Chen S, Arkin MR, Bogyo M, Deu E. PLoS One 14 e0226270 (2019)
  4. In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2. Hernández González JE, Salas-Sarduy E, Hernández Alvarez L, Barreto Gomes DE, Pascutti PG, Oostenbrink C, Leite VBP. J Comput Aided Mol Des 35 1067-1079 (2021)
  5. Enhancement of Inhibitory Activity by Combining Allosteric Inhibitors Putatively Binding to Different Allosteric Sites on Cathepsin K. Sato S, Yamamoto K, Ito M, Nishino K, Otsuka T, Irie K, Nagao M. Molecules 28 4197 (2023)


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