Protein binding domains stabilizing functional conformational states of GPCRs and uses thereof
First Claim
1. A complex comprising:
- a nanobody able to specifically bind to and stabilize an active conformational state of a beta 2 adrenergic receptor (β
2AR), wherein the nanobody is able to enhance the affinity of the β
2AR for an agonist, andβ
2AR in an active conformational state.
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Accused Products
Abstract
The disclosure relates to the field of GPCR structure biology and signaling. In particular, it relates to protein binding domains directed against or capable of specifically binding to a functional conformational state of a G-protein-coupled receptor (GPCR). More specifically, it provides protein binding domains that are capable of increasing the stability of a functional conformational state of a GPCR, in particular, increasing the stability of a GPCR in its active conformational state. The protein binding domains hereof can be used as a tool for the structural and functional characterization of G-protein-coupled receptors bound to various natural and synthetic ligands, as well as for screening and drug discovery efforts targeting GPCRs. Moreover, also encompassed are the diagnostic, prognostic and therapeutic usefulness of these protein binding domains for GPCR-related diseases.
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Citations
18 Claims
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1. A complex comprising:
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a nanobody able to specifically bind to and stabilize an active conformational state of a beta 2 adrenergic receptor (β
2AR), wherein the nanobody is able to enhance the affinity of the β
2AR for an agonist, andβ
2AR in an active conformational state. - View Dependent Claims (2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)
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6. A crystalline form of a complex comprising:
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(i) a nanobody able to specifically bind to and stabilize an active conformational state of a beta 2 adrenergic receptor (β
2AR), wherein the nanobody is able to enhance the affinity of the β
2AR for an agonist,(ii) a β
2AR in an active conformational state, and(iii) a ligand.
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18. A complex comprising:
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a nanobody able to specifically bind to and stabilize an active conformational state of a beta 2 adrenergic receptor (β
2AR), wherein the nanobody is able to enhance the affinity of the β
2AR for an agonist, anda β
2AR in an active conformational state, andwherein the nanobody is bound in the G protein binding site of the β
2AR;wherein the β
2AR is in a conformation where the cytoplasmic end of transmembrane segment 6 (TM6) is moved outward and away from the core of the β
2AR as compared to the β
2AR when not bound to the nanobody; andwherein the β
2AR has enhanced affinity for an agonist as compared to the β
2AR when not bound to the nanobody.
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Specification