Elucidation of stable intermediates in urea-induced unfolding pathway of human carbonic anhydrase IX.

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Prakash A, Dixit G, Meena NK, Singh R, Vishwakarma P, Mishra S, Lynn AM

Elucidation of stable intermediates in urea-induced unfolding pathway of human carbonic anhydrase IX.

J Biomol Struct Dyn. 2018 Jul;36(9):2391-2406. doi: 10.1080/07391102.2017.1355847. Epub 2017 Jul 28.

PubMed ID

28705076 [ View in PubMed

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Abstract

Human carbonic anhydrase IX (CAIX) has evolved as a promising biomarker for cancer prognosis, due to its overexpression in various cancers and restricted expression in normal tissue. However, limited information is available on its biophysical behavior. The unfolding of CAIX in aqueous urea solution was studied using all-atom molecular dynamics simulation approach. The results of this study revealed a stable intermediate state along the unfolding pathway of CAIX. At intermediate concentrations of urea (2.0-4.0 M), the protein displays a native-like structure with a large population of its secondary structure and hydrophobic contacts remaining intact in addition to small confined overall motions. Beyond 4.0 M urea, the unfolding is more gradual and at 8.0 M urea the structure is largely collapsed due to the solvent effect. The hydrophobic contact analysis suggests that the contact in terminal alpha-helices is separated initially which propagates in the loss of contacts from centrally located beta-sheets. The reduction of 60-65% tertiary contacts in 7.0-8.0 M urea suggested the presence of residual structure in unfolded state and is confirmed with structural snap shot. Free energy landscape analysis suggested that unfolding of CAIX exists through the different intermediate states.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Urea	Carbonic anhydrase 2	Protein	Humans	Unknown	Not Available	Details