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The structural and functional analysis of hOAT1 in complex with the high-affinity antihypertensive drug olmesartan provides a detailed blueprint for substrate specificity and binding. | The structural and functional analysis of hOAT1 in complex with the high-affinity antihypertensive drug olmesartan provides a detailed blueprint for substrate specificity and binding. | ||
'''Binding Location and Pose''' | |||
:*Olmesartan binds within the central cavity of hOAT1 in an inward-facing conformation. | :*Olmesartan binds within the central cavity of hOAT1 in an inward-facing conformation. | ||
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:*The drug adopts a diagonal orientation relative to the membrane plane, a pose that requires more space than the smaller inhibitor probenecid. This orientation is similar to its conformation when bound to the angiotensin receptor. | :*The drug adopts a diagonal orientation relative to the membrane plane, a pose that requires more space than the smaller inhibitor probenecid. This orientation is similar to its conformation when bound to the angiotensin receptor. | ||
''' Key Interacting Residues''' | |||
:*Olmesartan is surrounded by residues from multiple transmembrane helices (TM1, TM4, TM5, TM7, TM10, TM11) within a 5 Å distance. The critical interactions involve: | :*Olmesartan is surrounded by residues from multiple transmembrane helices (TM1, TM4, TM5, TM7, TM10, TM11) within a 5 Å distance. The critical interactions involve: | ||
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:*This suggests these residues not only form a gate but also directly interact with large, transportable substrates like olmesartan. | :*This suggests these residues not only form a gate but also directly interact with large, transportable substrates like olmesartan. | ||
''' Chloride Ion Coordination is Essential''' | |||
:*A key finding is the role of a chloride ion in stabilizing the olmesartan-bound state. | :*A key finding is the role of a chloride ion in stabilizing the olmesartan-bound state. | ||
