1RWE

Enhancing the activity of insulin at receptor edge: crystal structure and photo-cross-linking of A8 analogues

Summary for 1RWE

• Entry DOI: 10.2210/pdb1rwe/pdb
• Related: 1MPJ
• Descriptor: insulin, Insulin, ZINC ION, ... (6 entities in total)
• Functional Keywords: a8-histidine human insulin, insulin receptor, hormone-growth factor complex, hormone/growth factor
• Cellular location: Secreted: P01308 P01308
• Total number of polymer chains: 4
• Total formula weight: 12005.22

Authors

Wan, Z.,Xu, B.,Chu, Y.C.,Li, B.,Nakagawa, S.H.,Qu, Y.,Hu, S.Q.,Katsoyannis, P.G.,Weiss, M.A. (deposition date: 2003-12-16, release date: 2005-02-15, Last modification date: 2024-10-30)

Primary citation

Wan, Z.,Xu, B.,Huang, K.,Chu, Y.C.,Li, B.,Nakagawa, S.H.,Qu, Y.,Hu, S.Q.,Katsoyannis, P.G.,Weiss, M.A.
Enhancing the activity of insulin at the receptor interface: crystal structure and photo-cross-linking of A8 analogues.
Biochemistry, 43:16119-16133, 2004

PubMed Abstract: The receptor-binding surface of insulin is broadly conserved, reflecting its evolutionary optimization. Neighboring positions nevertheless offer an opportunity to enhance activity, through either transmitted structural changes or introduction of novel contacts. Nonconserved residue A8 is of particular interest as Thr(A8) --> His substitution (a species variant in birds and fish) augments the potency of human insulin. Diverse A8 substitutions are well tolerated, suggesting that the hormone-receptor interface is not tightly packed at this site. To resolve whether enhanced activity is directly or indirectly mediated by the variant A8 side chain, we have determined the crystal structure of His(A8)-insulin and investigated the photo-cross-linking properties of an A8 analogue containing p-azidophenylalanine. The structure, characterized as a T(3)R(3)(f) zinc hexamer at 1.8 A resolution, is essentially identical to that of native insulin. The photoactivatable analogue exhibits efficient cross-linking to the insulin receptor. The site of cross-linking lies within a 14 kDa C-terminal domain of the alpha-subunit. This contact, to our knowledge the first to be demonstrated from the A chain, is inconsistent with a recent model of the hormone-receptor complex derived from electron microscopy. Optimizing the binding interaction of a nonconserved side chain on the surface of insulin may thus enhance its activity.

PubMed: 15610006
DOI: 10.1021/bi048223f

Experimental method

X-RAY DIFFRACTION (1.8 Å)