Analysis of Cytochrome P450 CYP119 Ligand-dependent Conformational Dynamics by Two-dimensional NMR and X-ray Crystallography

Basudhar, Debashree; Madrona, Y.; Kandel, Sylvie E.; Lampe, Jed N.; Nishida, Clinton R.; Montellano, Paul R. Ortiz de

doi:10.1074/jbc.m114.627935

Cited by 30 publications

(33 citation statements)

References 64 publications

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“…Finally, work with bacterial P450 119 is of interest [111]. Crystal structures of P450 119 are known.…”

Section: General Phenomena Of P450 Reactions Studied By Structural Mementioning

confidence: 99%

“…Basudhar et al . [111] used a series of azole ligands and both X-ray crystallography and NMR with P450 119. They concluded that some azoles bound to the open form and that some substituted phenylimidazoles gave rise to two closed conformations that depended on the size of the para -substituent (PDB 4TT5, 4TUV, 4WPD, .4WQJ).…”

Section: General Phenomena Of P450 Reactions Studied By Structural Mementioning

confidence: 99%

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Recent Structural Insights into Cytochrome P450 Function

Guengerich

Waterman

Egli

2016

Trends in Pharmacological Sciences

287

178

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Cytochrome P450 (P450) enzymes are important in the metabolism of drugs, steroids, fat-soluble vitamins, carcinogens, pesticides, and many other types of chemicals. Their catalytic activities are important issues in areas such as drug-drug interactions and endocrine function. During the past 30 years, structures of P450s have been very helpful in understanding function, particularly the mammalian P450 structures available in the past 15 years. We review recent activity in this area, focusing on the past two years (2014–2015). Structural work with microbial P450s includes studies related to the biosynthesis of natural products and the use of parasitic and fungal P450 structures as targets for drug discovery. Studies on mammalian P450s include the utilization of information about ‘drug-metabolizing’ P450s to improve drug development and also to understand the molecular bases of endocrine dysfunction.

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“…Finally, work with bacterial P450 119 is of interest [111]. Crystal structures of P450 119 are known.…”

Section: General Phenomena Of P450 Reactions Studied By Structural Mementioning

confidence: 99%

Section: General Phenomena Of P450 Reactions Studied By Structural Mementioning

confidence: 99%

Recent Structural Insights into Cytochrome P450 Function

Guengerich

Waterman

Egli

2016

Trends in Pharmacological Sciences

287

178

View full text Add to dashboard Cite

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“…In this complex, it became clear that shortening the CPR hinge region leads to a protein that favors the open conformation and promotes association with HO (Sugishima et al, 2014). These studies demonstrate the utility of combining the power of Sevrioukova et al, 1997Cupp-Vickery et al, 2000;Hall et al, 2001;Podust et al, 2001;Yoshinari et al, 2001;Williams et al, 2003;Grahn et al, 2006;He et al, 2006;Deng et al, 2010;Wilderman et al, 2012;Hiruma et al, 2013;Tripathi et al, 2013;Peng et al, 2014;Sugishima et al, 2014;Basudhar et al, 2015;Reed and Backes, 2017;Gill, 1983;Kakuta et al, 1997;Meech and Mackenzie, 1997;Argiriadi et al, 1999;Binda et al, 2001Binda et al, , 2011…”

Section: X-ray Crystallographymentioning

confidence: 99%

“…Over the course of the previous two decades, X-ray crystallography has provided us with an enormous amount of information regarding protein structure in drug metabolizing enzymes (Cupp-Vickery et al, 2000;Podust et al, 2001;Yoshinari et al, 2001;Williams et al, 2003;Grahn et al, 2006;He et al, 2006;Wilderman et al, 2012;Basudhar et al, 2015), for a recent review in this area, see (Reed and Backes, 2017). Despite this, structures of multi-protein complexes involved in drug metabolism and disposition are exceedingly rare.…”

Section: X-ray Crystallographymentioning

confidence: 99%

“…A powerful and complementary technique to X-ray crystallography is protein NMR (Lampe et al, 2008(Lampe et al, , 2010Vallurupalli et al, 2008;Raman et al, 2010;Ahuja et al, 2013;Hiruma et al, 2013;Basudhar et al, 2015). In particular, solution NMR can report not only on protein tertiary structure, but also on conformational dynamics which are important to the interaction with protein partners (Lampe et al, 2008(Lampe et al, , 2010).…”

Section: Nuclear Magnetic Resonance (Nmr)mentioning

confidence: 99%

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Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

Pandey¹,

Henderson²,

Ishii³

et al. 2018

Frontiers Research Topics

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Directed Evolution of Artificial Metalloenzymes in Whole Cells

Bloomer

Liu

et al. 2021

Angewandte Chemie

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Artificial metalloenzymes (ArMs), created by introducing synthetic cofactors into protein scaffolds,a re an emerging class of catalyst for non-natural reactions.Although many classes of ArMs are known, in vitro reconstitution of cofactors and proteins has been al imiting step in the highthroughput screening and directed evolution of ArMs because purification of individual host proteins is time-consuming. We describe the application of ap latform to combine mutants of the P450 enzyme CYP119 and the cofactor Ir(Me)MPIX in vivo,b yc oexpression of the CYP119 mutants with the heme transporter encoded by the hug operon, to the directed evolution of ArMs containing Ir(Me)MPIX in whole cells. We applied this platform to the development an ArMs catalyzing the insertion of the acyclic carbene from adiazopropanoate esters (Me-EDA) into the N À Hb onds of N-alkyl anilines,acombination of carbene and amine classes for which mutant enzymes of natural hemoproteins previously reacted with lowenantioselectivity.The mutants of the artificial metalloenzyme Ir(Me)CYP119 identified by an evolution campaign involving more than 4000 mutants are shown to catalyze the reaction of Me-EDAw ith N-methyl anilines to form chiral chiral amino esters with high TONa nd good enantioselectivity,t hereby demonstrating that the directed evolution of ArMs can rival that of natural enzymes in vivo.

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Analysis of Cytochrome P450 CYP119 Ligand-dependent Conformational Dynamics by Two-dimensional NMR and X-ray Crystallography

Cited by 30 publications

References 64 publications

Recent Structural Insights into Cytochrome P450 Function

Recent Structural Insights into Cytochrome P450 Function

Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

Directed Evolution of Artificial Metalloenzymes in Whole Cells

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