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--- structure [2025/07/25 08:01] – jasoncharamis
+++ structure [2026/02/17 13:08] (current) – renefeyereisen
@@ Line 69: / Line 69: @@
 Zawaira et al., (2011) took advantage of about 50 crystal structures of mammalian P450s, versus just the bacterial P450cam structure available to Gotoh in 1992. They revisited the SRS concept by combining what they called "X-ray structures SRS maps" and substrate "docking SRS maps" for a number of P450s from four families. From this much larger sample than Gotoh's original study, Zawaira et al. (2011) modified and expanded the SRS zones to 33% of the mammalian P450 sequences. It would seem therefore that, by covering a third of the primary structure of P450s, such a new SRS definition can only be less relevant than Gotoh's landmark SRSs. Instead, given the increasingly accurate and family-specific structural information that is now available, defining regions of the P450 structure that interact with substrates (and inhibitors) can be done more directly than by relying on an SRS template. However, until now mammalian structures from the CYP2, 3 or 4 clans remain the best, yet only distant templates for arthropod P450s.
+===== Modeling arthropod P450s =====
+In the absence of X-ray structures for any arthropod P450s, any modeling relies on homologies with known but distant structures as computed by (increasingly) sophisticated programs. For instance, the alignment of arthropod P450s to the sequence of the closest vertebrate P450s of known structure reveals very low % of positional identity (e.g. fly CYP6A1 / human CYP3A4 : 29.3% ; mite 392A11 / human CYP2B6 : 27.2%).
+The illustrative value of such models can serve to support or guide site-directed mutagenesis studies as well as inform on the potential effect of naturally occurring mutations. Studies relying on docking of potential substrates on P450 models have little intrinsic value in the absence of strong experimental evidence of function. Unfortunately, too many studies misuse modeling techniques, notably by reporting docking to P450 models lacking a correctly positioned heme cofactor, docking to the surface of the modeled P450, or even docking beneath the surface of the heme. More seriously, modeling studies have difficulties dealing with conformational changes in P450 structure that are known to result from substrate binding, redox partner binding, the membrane environment, or P450-P450 interactions.
+Progress in the rational use of P450 models is currently best exemplified by the study of [[https://doi.org/10.1016/j.pestbp.2025.106816|Hayward et al. (2026)]] who present a detailed pipeline for modeling studies.