6AX7

The crystal structure of a lysyl hydroxylase from Acanthamoeba polyphaga mimivirus

Summary for 6AX7

• Entry DOI: 10.2210/pdb6ax7/pdb
• Descriptor: Procollagen lysyl hydroxylase and glycosyltransferase, FE (II) ION (3 entities in total)
• Functional Keywords: double-stranded ?-helix, dimer, dioxygenase, collagen, oxidoreductase
• Biological source: Acanthamoeba polyphaga mimivirus (APMV)
• Total number of polymer chains: 2
• Total formula weight: 54803.34

Authors

Guo, H.,Tsai, C.,Miller, M.D.,Alvarado, S.,Tainer, J.A.,Phillips Jr., G.N.,Kurie, J.M. (deposition date: 2017-09-06, release date: 2018-02-21, Last modification date: 2023-10-04)

Primary citation

Guo, H.F.,Tsai, C.L.,Terajima, M.,Tan, X.,Banerjee, P.,Miller, M.D.,Liu, X.,Yu, J.,Byemerwa, J.,Alvarado, S.,Kaoud, T.S.,Dalby, K.N.,Bota-Rabassedas, N.,Chen, Y.,Yamauchi, M.,Tainer, J.A.,Phillips, G.N.,Kurie, J.M.
Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+-binding.
Nat Commun, 9:512-512, 2018

PubMed Abstract: Collagen lysyl hydroxylases (LH1-3) are Fe- 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 Å 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 β-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 Fe. The two active sites flank a deep surface cleft that suggest dimerization creates a collagen-binding site. Loss of Fe-binding disrupts the dimer. Dimer disruption and charge reversal in the cleft increase K and reduce LH activity. Ectopic L230 expression in tumors promotes collagen cross-linking and metastasis. These insights suggest inhibitor targets for fibrosis and cancer.

PubMed: 29410444
DOI: 10.1038/s41467-018-02859-z

Experimental method

X-RAY DIFFRACTION (2.002 Å)