HOAT1: Difference between revisions

Line 118:

*Its binding site overlaps with both Site 1 (partially) and Site 3.

*In the binding pocket of Site 1, surrounded by 16 residues located within a 5 A ˚ (M31, N35, M142, V145, G227, Y230, W346, Y353, Y354, K382, D378, F438, S462, A465, R466, and S469).

*It engages in specific, high-affinity interactions with key residues:

Line 137:

Line 139:

:*'''Path A''' (between TM2 and TM11) is narrowed from ~5 Å to ~4 Å.

:*'''Path B''' (between TM5 and TM8) is completely blocked.

:*'''Path B''' (between TM5 and TM8) is completely blocked. Restriction of the access route to path B likely limits the entry of substrates to Site 1 and the exit of substrates from the binding pocket.

This structural rearrangement is caused by a slight inward movement of the cytoplasmic ends of TM5, TM8, TM10, and TM11 toward the binding pocket.

'''3. Locked Conformation'''

By constricting the cytoplasmic access routes, probenecid does not just compete for the substrate-binding site; it stabilizes the transporter in an apo-like, inward-facing conformation that is inaccessible to cytosolic substrates. This prevents the entry of new substrates and likely traps the transporter in this non-functional state, effectively "locking" it and preventing the conformational changes necessary for the transport cycle.

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@@ Line 118: / Line 118: @@
 *Its binding site overlaps with both Site 1 (partially) and Site 3.
+*In the binding pocket of Site 1, surrounded by 16 residues located within a 5 A ˚ (M31, N35, M142, V145, G227, Y230, W346, Y353, Y354, K382, D378, F438, S462, A465, R466, and S469).
 *It engages in specific, high-affinity interactions with key residues:
@@ Line 137: / Line 139: @@
 :*'''Path A''' (between TM2 and TM11) is narrowed from ~5 Å to ~4 Å.
-:*'''Path B''' (between TM5 and TM8) is completely blocked.
+:*'''Path B''' (between TM5 and TM8) is completely blocked. Restriction of the access route to path B likely limits the entry of substrates to Site 1 and the exit of substrates from the binding pocket.
 This structural rearrangement is caused by a slight inward movement of the cytoplasmic ends of TM5, TM8, TM10, and TM11 toward the binding pocket.
 '''3. Locked Conformation'''
+By constricting the cytoplasmic access routes, probenecid does not just compete for the substrate-binding site; it stabilizes the transporter in an apo-like, inward-facing conformation that is inaccessible to cytosolic substrates. This prevents the entry of new substrates and likely traps the transporter in this non-functional state, effectively "locking" it and preventing the conformational changes necessary for the transport cycle.