Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-02859-z
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Funding
- National Institutes of Health [R21AR060978, R01CA105155, P50CA70907]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP160652]
- International Association for the Study of Lung Cancer Postdoctoral Fellowship
- Elza A. and Ina S. Freeman Professorship in Lung Cancer
- The Welch Foundation [F-1390]
- NIH [GM123252]
- CPRIT [RP160657]
- Department of Energy Office of Biological and Environmental Research, National Institute of Health [R01GM105404, S10OD018483]
- NATIONAL CANCER INSTITUTE [R01CA105155, P50CA070907] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R21AR060978] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM105404, P30GM124169, T32GM008280, R01GM123252] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD018483] Funding Source: NIH RePORTER
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Collagen lysyl hydroxylases (LH1-3) are Fe2+-and 2-oxoglutarate (2-OG)-dependent oxygenases that maintain extracellular matrix homeostasis. High LH2 levels cause stable collagen cross-link accumulations that promote fibrosis and cancer progression. However, developing LH antagonists will require structural insights. Here, we report a 2 angstrom crystal structure and X-ray scattering on dimer assemblies for the LH domain of L230 in Acanthamoeba polyphaga mimivirus. Loop residues in the double-stranded beta-helix core generate a tail-to-tail dimer. A stabilizing hydrophobic leucine locks into an aromatic tyrosine-pocket on the opposite subunit. An active site triad coordinates Fe2+. The two active sites flank a deep surface cleft that suggest dimerization creates a collagen-binding site. Loss of Fe2+-binding disrupts the dimer. Dimer disruption and charge reversal in the cleft increase Km and reduce LH activity. Ectopic L230 expression in tumors promotes collagen cross-linking and metastasis. These insights suggest inhibitor targets for fibrosis and cancer.
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