+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity

, : Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity. Journal of Biological Chemistry 291(22): 11876-11886

Cytochrome P450 46A1 (CYP46A1) is a microsomal enzyme and cholesterol 24-hydroxylase that controls cholesterol elimination from the brain. This P450 is also a potential target for Alzheimer disease because it can be activated pharmacologically by some marketed drugs, as exemplified by efavirenz, the anti-HIV medication. Previously, we suggested that pharmaceuticals activate CYP46A1 allosterically through binding to a site on the cytosolic protein surface, which is different from the enzyme active site facing the membrane. Here we identified this allosteric site for efavirenz on CYP46A1 by using a combination of hydrogen-deuterium exchange coupled to MS, computational modeling, site-directed mutagenesis, and analysis of the CYP46A1 crystal structure. We also mapped the binding region for the CYP46A1 redox partner oxidoreductase and found that the allosteric and redox partner binding sites share a common border. On the basis of the data obtained, we propose the mechanism of CYP46A1 allostery and the pathway for the signal transmission from the P450 allosteric site to the active site.


PMID: 27056331

DOI: 10.1074/jbc.M116.723577

Other references

Hou, H.; Wei, Y.; Song, Y.; Mi, L.; Tang, M.; Li, L.; Fan, Y., 2005: Metal ions play different roles in the third-order nonlinear optical properties of d10 metal-organic clusters. Angewandte Chemie 44(37): 6067-6074

Rainey J.M.Jr; Manov G.; Aleem A.; Toth A., 1990: Relationships between post traumatic stress disorder and panic disorder concurrent psychiatric illness effects of lactate infusions and erythrocyte lactate production. Ballenger, J C (Ed ) Frontiers Of Clinical Neuroscience, Vol 9 Clinical Aspects Of Panic Disorder Xv+328p Wiley-Liss: New York, New York, Usa; Chichester, England, Uk Illus 47-54

Struckmann, J.R.; Bruhn, B.F.; Hansen, H.S.; Olsen, P.R., 1980: Bilateral renal hemangioma. Ugeskrift for Laeger 142(19): 1226-1228

Papke, R.L., 2010: alpha4beta2 Nicotinic acetylcholine receptors, willing if able. Li and Steinbach apply nonstationary noise analysis to the whole-cell current responses of low sensitivity alpha4beta2 nAChR stably-expressed in HEK cells. These receptors represent one of the most important nAChR subtypes in brain, and also one o...

Vepkhvadze, L.K., 1978: Kinetics of feulgen reaction hydrolysis of the hepatocytes of chick embryos in different periods of incubation. The kinetics of Feulgen acid hydrolysis for the DNA of chick embryo hepatic cells were studied. Maxima (3) were found on the hydrolysis curves. These maxima correspond to components of chromatin, differing in their sensitivity to acid hydrolysis....

L.R.un, E.; Zairi, F., 2013: Treatment of the leptomeningeal metastases related to solid tumors. The incidence of metastases of the central nervous system (CNS) is increasing, due to the improvement of the overall survival of cancer patients. Leptomeningeal metastases (LM) are now more often identified, although the criteria used for the diag...

Gilbert, R.W.; Lundgren, J.A.; van Nostrand, A.W.; Keane, T.J., 1988: T3N0M0 glottic carcinoma--a pathologic analysis of 41 patients treated surgically following radiotherapy. Forty-one patients undergoing surgery for recurrent or residual tumour following radical radiotherapy for T3N0M0 glottic carcinoma had their larynges evaluated pathologically by whole organ laryngeal sectioning. All patients had been staged initia...

Kloner, R.A.; Tubau, J.F., 1994: Application of nuclear cardiology to the diagnosis of stunned and hibernating myocardium. Journal of Nuclear Cardiology 1(5 Pt 1): 490-491

Ribeiro, M.; Pereira, C.A.C.; Nery, L.E.; Beppu, O.S.; Silva, C.O.S., 2008: Methacholine vs adenosine on intra and extrathoracic airway hyperresponsiveness in patients with cough variant asthma. Background: Airway hyperresponsiveness (AHR) can be studied by bronchoprovocation test (BPT) using direct (methacholine - MCh) or indirect (adenosine 5'-monophosphate - AMP) stimuli. These two substances have not been compared in cough varia...

Kvyatkovskii, E.A.; Kharkhota, V.B., 1998: Diagnosis of acutely congestive kidney in nephritic colic made with the aid of Doppler ultrasound. Twenty patients free from urodynamic disturbances and 26 patients presenting with nephritic colic were studied in an ultrasound investigation into the urinary system and renal arteries. The examinees divided into the following groups: controls, pa...