A molecular model of human Lysyl Oxidase (LOX) with optimal copper orientation in the catalytic cavity for induced fit docking studies with potential modulators

Renganathan, Bhuvanasundar; John, Arun; Sulochana, K N; Coral, Karunakaran; Deepa, Perinkulam Ravi; Vetrivel, Umashankar

doi:10.6026/97320630010406

Cited by 18 publications

(17 citation statements)

References 25 publications

(30 reference statements)

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“…Furthermore, it is difficult to compare the content in secondary structures and random coils of our model with Kagan and Ryvkin’s model because the total amount of secondary structures of their model was higher than 100% (110%: 20% α-helices, 25% β-strands, 65% random coil, and turns). On the other hand, our model contains less secondary structures than Bhuvanasundar’s model 36 (24 and 25% of α-helices and β-strands, respectively, for their model versus 9.2 and 18.9% of α-helices and β-strands, respectively, for our model). The values calculated from the deconvolution of circular dichroism spectra of human LOX are twice higher than in our model for α-helices (21%) and in the same range for β-strands 26 (27.5%).…”

Section: Discussionmentioning

confidence: 55%

“…Furthermore, Kagan and Ryvkin did not perform molecular dynamics simulations to assess the structural stability of their model. The second published model 36 was built ab initio with the Robetta server and refined with MAESTRO 9.3 but does not contain the LTQ cofactor. 36 A very short dynamics simulation (4 ns) was performed, but it was not sufficient to evaluate the stability of the proposed model, and the fluctuations during the trajectory were not reported.…”

Section: Discussionmentioning

confidence: 99%

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A Three-Dimensional Model of Human Lysyl Oxidase, a Cross-Linking Enzyme

et al. 2019

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Lysyl oxidase (LOX) is a cross-linking enzyme identified 50 years ago, but its 3D structure is still unknown. We have thus built a 3D model of human LOX by homology modeling using the X-ray structure of human lysyl oxidase-like 2 as a template. This model is the first one to recapitulate all known biochemical features of LOX, namely, the coordination of the copper ion and the formation of the lysine tyrosylquinone cofactor and the disulfide bridges. Furthermore, this model is stable during a 1 μs molecular dynamics simulation. The catalytic site is located in a groove surrounded by two loops. The distance between these loops fluctuated during the simulations, which suggests that the groove forms a hinge with a variable opening, which is able to accommodate the various sizes of LOX substrates. This 3D model is a pre-requisite to perform docking experiments with LOX substrates and other partners to identify binding sites and to design new LOX inhibitors specific for therapeutic purpose.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

A Three-Dimensional Model of Human Lysyl Oxidase, a Cross-Linking Enzyme

et al. 2019

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“…LOXs are copper-dependent enzymes. Copper ion binding to pro-LOX is necessary for LOX activation (9,18). The most well-studied roles of LOX enzymes are in the remodeling of the ECM and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Copper is a factor that binds to selected enzymes and functions to increase their activation. For example, Lysyl oxidase (LOX) is the prototypical member of copperdependent enzymes whose documented function is to oxidize primary amine substrates to reactive aldehydes (9). The most well-characterized role of LOX is in the remodeling of the extracellular matrix (ECM) through the oxidative deamination of peptidyl lysine residues in collagens and elastin to facilitate covalent cross-linking (10).…”

Section: Introductionmentioning

confidence: 99%

Ammonium tetrathiomolybdate enhances the antitumor effects of cetuximab via the suppression of osteoclastogenesis in head and neck squamous carcinoma

et al. 2018

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Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically where one of the mechanisms responsible for the invasion into facial bones occurs via the activation of osteoclasts. Copper has been demonstrated to play a key role in skeletal remodeling. However, the role of copper in cancer-associated bone destruction is thus far unknown. Lysyl oxidase (LOX) is a copper-dependent enzyme that promotes osteoclastogenesis. In the present study, we investigated the effects of copper on HNSCC with bone invasion by the copper chelator, ammonium tetrathiomolybdate (TM) in vitro and in vivo. We demonstrate that TM blocks the proliferation of HNSCC cells, inhibits LOX activation and decreases the expression of the receptor activator of nuclear factor-κB ligand (RANKL) in osteoblasts and osteocytes, subsequently suppressing bone destruction. These findings suggest that copper is a potential target for the treatment of HNSCCs associated with bone destruction.

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“…83,84 Cancer cells are known to secrete LOX, which enables tumour cells to effectively alter the extracellular matrix such that a pre-metastatic stage eventuates. Importantly, copper is a requirement for the enzymatic activity of both lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins that are involved in crosslinking of collagen and elastin fibres.…”

Section: Copper and Metastasismentioning

confidence: 99%

Copper and conquer: copper complexes of di-2-pyridylketone thiosemicarbazones as novel anti-cancer therapeutics

et al. 2016

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Copper is an essential trace metal required by organisms to perform a number of important biological processes. Copper readily cycles between its reduced Cu(i) and oxidised Cu(ii) states, which makes it redox active in biological systems. This redox-cycling propensity is vital for copper to act as a catalytic co-factor in enzymes. While copper is essential for normal physiology, enhanced copper levels in tumours leads to cancer progression. In particular, the stimulatory effect of copper on angiogenesis has been established in the last several decades. Additionally, it has been demonstrated that copper affects tumour growth and promotes metastasis. Based on the effects of copper on cancer progression, chelators that bind copper have been developed as anti-cancer agents. In fact, a novel class of thiosemicarbazone compounds, namely the di-2-pyridylketone thiosemicarbazones that bind copper, have shown great promise in terms of their anti-cancer activity. These agents have a unique mechanism of action, in which they form redox-active complexes with copper in the lysosomes of cancer cells. Furthermore, these agents are able to overcome P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) and act as potent anti-oncogenic agents through their ability to up-regulate the metastasis suppressor protein, N-myc downstream regulated gene-1 (NDRG1). This review provides an overview of the metabolism and regulation of copper in normal physiology, followed by a discussion of the dysregulation of copper homeostasis in cancer and the effects of copper on cancer progression. Finally, recent advances in our understanding of the mechanisms of action of anti-cancer agents targeting copper are discussed.

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A molecular model of human Lysyl Oxidase (LOX) with optimal copper orientation in the catalytic cavity for induced fit docking studies with potential modulators

Cited by 18 publications

References 25 publications

A Three-Dimensional Model of Human Lysyl Oxidase, a Cross-Linking Enzyme

A Three-Dimensional Model of Human Lysyl Oxidase, a Cross-Linking Enzyme

Ammonium tetrathiomolybdate enhances the antitumor effects of cetuximab via the suppression of osteoclastogenesis in head and neck squamous carcinoma

Copper and conquer: copper complexes of di-2-pyridylketone thiosemicarbazones as novel anti-cancer therapeutics

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