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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	Functional and structural characterisation of a viral cytochrome b5 Emma L. Reid , Karen D. Weynberg , John Love , Misha Isupov , Jennifer A. Littlechild , William H. Wilson , Steven L. Kelly , David Lamb , Michael J. Allen Febs Letters 587 (22), 3633-3639 DOI: 10.1016/j.febslet.2013.09.035 PMID: 24100138 Diamond Proposal Number(s): [4173] Show Abstract ▼ Abstract: Cytochrome b5 is a ubiquitous electron transport protein. The sequenced viral OtV-2 genome, which infects Ostreococcus tauri, was predicted to encode a putative cytochrome b5 enzyme. Using purified OtV-2 cytochrome b5 we confirm this protein has identical spectral properties to purified human cytochrome b5 and additionally that the viral enzyme can substitute for yeast cytochrome b5 in yeast cytochrome P450 51 mediated sterol 14a-demethylation. The crystal structure of the OtV-2 cytochrome b5 enzyme reveals a single domain, comprising four b sheets, four a helices and a haem moiety, which is similar to that found in larger eukaryotic cytochrome proteins. As a product of a horizontal gene transfer event involving a subdomain of the host fumarate reductase-like protein, OtV-2 cytochrome b5 appears to have diverged in function and is likely to have evolved an entirely new role for the virus during infection. Indeed, lacking a hydrophobic C-terminal anchor, OtV-2 encodes the first cytosolic cytochrome b5 characterised. The lack of requirement for membrane attachment (in contrast to all other microsomal cytochrome b5s) may be a reflection of the small size of the host cell, further emphasizes the unique nature of this virus gene product and draws attention to the potential importance of cytochrome b5 metabolic activity at the extremes of cellular scale.	Oct 2013
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	An Enlarged, Adaptable Active Site in CYP164 Family P450 Enzymes, the Sole P450 in Mycobacterium leprae Christopher Agnew , Andrew Warrilow , Nick Burton , David Lamb , Steven Kelly , Leo Brady Antimicrobial Agents And Chemotherapy 56 (1), 391-402 DOI: 10.1128/AAC.05227-11 PMID: 22037849 Show Abstract ▼ Abstract: CYP164 family P450 enzymes are found in only a subset of mycobacteria and include CYP164A1, which is the sole P450 found in Mycobacterium leprae, the causative agent of leprosy. This has previously led to interest in this enzyme as a potential drug target. Here we describe the first crystal structure of a CYP164 enzyme, CYP164A2 from Mycobacterium smegmatis. CYP164A2 has a distinctive, enlarged hydrophobic active site that extends above the porphyrin ring toward the access channels. Unusually, we find that CYP164A2 can simultaneously bind two econazole molecules in different regions of the enlarged active site and is accompanied by the rearrangement and ordering of the BC loop. The primary location is through a classic interaction of the azole group with the porphyrin iron. The second econazole molecule is bound to a unique site and is linked to a tetracoordinated metal ion complexed to one of the heme carboxylates and to the side chains of His 105 and His 364. All of these features are preserved in the closely homologous M. leprae CYP164A1. The computational docking of azole compounds to a homology model of CYP164A1 suggests that these compounds will form effective inhibitors and is supported by the correlation of parallel docking with experimental binding studies of CYP164A2. The binding of econazole to CYP164A2 occurs primarily through the high-spin “open” conformation of the enzyme (Kd [dissociation constant] of 0.1 ?M), with binding to the low-spin “closed” form being significantly hindered (Kd of 338 ?M). These studies support previous suggestions that azole derivatives may provide an effective strategy to improve the treatment of leprosy.	Jan 2012

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