Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in a precursor state

Zhang, Xi; Wang, Qifan; Wu, Jianping; Wang, Jiawei; Shi, Yigong; Liu, Minhao

doi:10.1073/pnas.1720859115

Cited by 60 publications

(103 citation statements)

References 46 publications

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“…LOXL2 is the most extensively studied member of the family and may be a suitable potential target for cancer therapy. These SRCR domains within LOXL2 are thought to be involved in the interactions between proteins in the extracellular matrix (ECM) and cell‐surface proteins . The catalytic domain of LOXL2 is 88% and 86% similar to LOXL3 and LOXL4, respectively .…”

Section: Lysyl Oxidase‐likementioning

confidence: 99%

“…Importantly, the copper binding, histidine rich, site of h LOXL2 is occupied by Zinc 2+ which prevents LTQ generation. The crystal structure of LOXL2 in its functional state (with LTQ cofactor) has to date eluded solution . This precursor crystal structure of LOXL2 has, however, assisted in generating a 3D model for the LOX family …”

Section: Lysyl Oxidase‐likementioning

confidence: 99%

“…The LTQ region in LOXL2 is defined by the residues Y689 and K653 (Figure ) . The primary role of LOX enzymes is to catalyze the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin of the extracellular matrix (ECM).…”

Section: Lysyl Oxidase‐likementioning

confidence: 99%

“…As a consequence, the reactive aldehyde, allysine is formed which can create intermolecular and intramolecular covalent bonds with other lysine or allysine residues, cross‐linking the ECM. This is an important role in the formation and repair of the ECM network and the construction of connecting tissues …”

Section: Lysyl Oxidase‐likementioning

confidence: 99%

“…These SRCR domains within LOXL2 are thought to be involved in the interactions between proteins in the extracellular matrix (ECM) and cell-surface proteins. [19,21,22] The catalytic domain of LOXL2 is 88% and 86% similar to LOXL3 and LOXL4, respectively. [23] However, for LOX and LOXL1, LOXL2 is 68% and 66% similar, respectively.…”

Section: Cellular Migrationmentioning

confidence: 99%

See 4 more Smart Citations

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Chopra

Sangarappillai

Romero‐Canelón

et al. 2020

Advanced Therapeutics

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Lysyl oxidase‐like 2 (LOXL2) is an emerging drug target against metastatic disease owing to its role in the upregulation of key processes including epithelial‐mesenchymal transition (EMT) and invasion. Recent activity in the field of small molecule LOXL2 inhibitor development by pharmaceutical and academic laboratories has renewed interest in targeting LOXL2. Herein, 1) the viability of LOXL2 as a drug target for the treatment of metastatic disease through an investigation of its biological actions is determined; 2) the pitfalls of an antibody approach are considered; and 3) the small molecule approaches emerging in the scientific and patent literature are reviewed. This review identifies that LOXL2 is localized and active intracellularly and extracellularly in invasive cancer cells. LOXL2 has been implicated in a number of established signaling pathways involved in tumor progression, further highlighting its appeal as a target in metastatic disease. Previously, limited chemical inhibitors have been developed; however, their selectivity profile for the LOX family has proven controversial. Antibodies, such as simtuzumab, have been developed selectively against LOXL2. Simtuzumab, in particular, progresses into phase II trials but it was ultimately terminated. The small molecule inhibitors of LOXL2 are summarized, some of which are now in the early stages of clinical trials.

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Section: Lysyl Oxidase‐likementioning

confidence: 99%

Section: Lysyl Oxidase‐likementioning

confidence: 99%

Section: Lysyl Oxidase‐likementioning

confidence: 99%

Section: Lysyl Oxidase‐likementioning

confidence: 99%

Section: Cellular Migrationmentioning

confidence: 99%

See 3 more Smart Citations

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Chopra

Sangarappillai

Romero‐Canelón

et al. 2020

Advanced Therapeutics

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Protein‐Derived Cofactors

Davidson¹

2020

Encyclopedia of Life Sciences

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Protein‐derived cofactors are catalytic or redox‐active centres in proteins that are formed by covalent irreversible posttranslational modification of one or more amino acid residues. The mechanisms by which these posttranslational modifications are catalysed are quite diverse. In some cases, these modifications occur autocatalytically, and in other cases, an enzyme is required for their catalysis. The formation of protein‐derived cofactors expands the range of chemical reactions that may be catalysed by enzymes in the absence of exogenous metal or organic cofactors. Protein‐derived cofactors typically function as electrophiles in catalysis and sometimes stabilise free‐radical intermediates or mediate biological electron transfer. This article describes the structures and functions of several protein‐derived cofactors and the diverse mechanisms of posttranslational modification through which they are generated. Key Concepts Protein‐derived cofactors are formed by irreversible posttranslational modification of amino acid residues. Protein‐derived cofactors typically serve as electrophiles or stabilise free radicals during enzyme catalysis. Amino acid residues may acquire new catalytic or redox functions from posttranslational modification. Modification of amino acids that provide ligands for metals can alter the properties of metalloenzymes. Protein‐derived cofactors are formed by a variety of autocatalytic and enzyme‐catalysed processes.

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Conformation Changes Associated with the Formation and Activation of Lysine Tyrosylquinone of LOXL2 Studied by Metadynamics Simulation

Wang,

Lin,

et al. 2024

Advcd Theory and Sims

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Lysyl oxidase‐like 2 (LOXL2) is a Cu2+‐dependent amine oxidase that catalyzes the oxidative deamination of lysine residues of elastin and collagen to generate aldehyde groups. In the active state of LOXL2, its conserved catalytic domain has a lysine tyrosylquinone (LTQ) cofactor and a copper ion. LTQ is post‐translationally derived from Lys653 and Tyr689 of LOXL2. In this study, well‐tempered metadynamics simulations are used to investigate the conformation modulation from the inactive state to active state and obtain the free energy landscape. Interestingly, the simulations show that LTQ precursor residues cannot get close in Zn2+−bound LOXL2, whereas the copper ion binding triggers a conformation change to form an optional structure for LTQ biosynthesis. It is found that a prominent loop, consisting of residues 654–658, hinders the formation of LTQ in Zn2+−LOXL2 by preventing Lys653 from moving into active site of LOXL2, whereas this loop is relatively flexible in Cu2+−LOXL2. After the formation of LTQ, it needs to be activated by adjusting its position to be exposed to the solvent, thus allowing it to react with its substrate proteins. The results indicate that this process involves an intermediate state and that the activation of LTQ overcomes an energy barrier of 5.9 kcal mol−1.

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Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in a precursor state

Cited by 60 publications

References 46 publications

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Protein‐Derived Cofactors

Conformation Changes Associated with the Formation and Activation of Lysine Tyrosylquinone of LOXL2 Studied by Metadynamics Simulation

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