PTCH1
December 2021
Patched 1 (PTCH1) is a member of the patched family transporters contributing to cancer-cell chemotherapy resistance.
PTCH1 plays a negative regulatory role in the Hedgehog signaling pathway by inhibiting the GPCR-like protein Smoothened (SMO). When the Hedgehog (Hh) protein binds to PTCH1, however, the inhibition of SMO stops, and the signaling pathway gets activated. The Hh pathway is involved in embryogenesis, tissue regeneration, and stem cell homeostasis.
The dysregulation of Hh signaling promotes uncontrolled cell proliferation associated with various cancers in which PTCH1 is overexpressed.
PTCH1 is believed to inhibit SMO by transporting cholesterol (and derivatives). Due to efflux, the cholesterol level around SMO decreases and SMO gets inhibited.
In addition to the sterol transport role, it has been recently demonstrated that PTCH1 transports multiple chemotherapeutic drugs out of the cancer cells. Since PTCH1 is overexpressed in cancer cells, as previously mentioned, it contributes to multidrug chemotherapy resistance.
PTCH1 is a large protein that consists of a transmembrane (TM) domain with 12 TM helices and two extracellular domains that include ECD1 (located between TM1 and TM2) and ECD2 (TM7 and TM8). The TMs 2 to 6 constitute the sterol-sensing domain (SSD) and hold the cholesterol-binding pocket. The proton relay site (PRS) on PTCH1 indicates that the cholesterol/drug transport is driven by proton exchange.
Nevertheless, the exact way of how PTCH1 transports cholesterol/drugs is still not completely clear. Therefore, scientists are working on understanding the structural basis of the PTCH1 drug efflux mechanism and are developing PTCH1 drug efflux inhibitors that will overcome the resistance, once used in combination with chemotherapy.
To get structural insights on the PTCH1 transport mechanism of cholesterol efflux and subsequently study the drug efflux mechanism, one could perform molecular dynamics (MD) studies on PTCH1.
Relation of the MD derived structures
To easily organize relevant structural snapshots obtained from the MD trajectories, you can use the Upload and Relate structures in 3decision. Instead of storing massive data in folders and easily getting lost in the crowd, the structures from the MD analysis can be related to the deposited original PDB entry. Moreover, you can add proper description described (even including the location of stored trajectories) for easier navigation. Keeping a trace of the generated files and relations between structures will save a lot of time on manual work and speed up the project progress. Ultimately, having a unique place to store and organize new data facilitates overall project overview and management.