5UDP

High resolution x-ray crystal structure of synthetic insulin lispro

Summary for 5UDP

• Entry DOI: 10.2210/pdb5udp/pdb
• Descriptor: Insulin Lispro A chain, Insulin Lispro B chain, PHENOL, ... (7 entities in total)
• Functional Keywords: insulin lispro, chemical protein synthesis, fmoc chemistry, hormone
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P01308 P01308
• Total number of polymer chains: 12
• Total formula weight: 35695.29

Authors

Mandal, K.,Dhayalan, B.,Kent, S.B.H. (deposition date: 2016-12-28, release date: 2017-01-11, Last modification date: 2024-11-20)

Primary citation

Dhayalan, B.,Mandal, K.,Rege, N.,Weiss, M.A.,Eitel, S.H.,Meier, T.,Schoenleber, R.O.,Kent, S.B.
Scope and Limitations of Fmoc Chemistry SPPS-Based Approaches to the Total Synthesis of Insulin Lispro via Ester Insulin.
Chemistry, 23:1709-1716, 2017

PubMed Abstract: We have systematically explored three approaches based on 9-fluorenylmethoxycarbonyl (Fmoc) chemistry solid phase peptide synthesis (SPPS) for the total chemical synthesis of the key depsipeptide intermediate for the efficient total chemical synthesis of insulin. The approaches used were: stepwise Fmoc chemistry SPPS; the "hybrid method", in which maximally protected peptide segments made by Fmoc chemistry SPPS are condensed in solution; and, native chemical ligation using peptide-thioester segments generated by Fmoc chemistry SPPS. A key building block in all three approaches was a Glu[O-β-(Thr)] ester-linked dipeptide equipped with a set of orthogonal protecting groups compatible with Fmoc chemistry SPPS. The most effective method for the preparation of the 51 residue ester-linked polypeptide chain of ester insulin was the use of unprotected peptide-thioester segments, prepared from peptide-hydrazides synthesized by Fmoc chemistry SPPS, and condensed by native chemical ligation. High-resolution X-ray crystallography confirmed the disulfide pairings and three-dimensional structure of synthetic insulin lispro prepared from ester insulin lispro by this route. Further optimization of these pilot studies could yield an efficient total chemical synthesis of insulin lispro (Humalog) based on peptide synthesis by Fmoc chemistry SPPS.

PubMed: 27905149
DOI: 10.1002/chem.201605578

Experimental method

X-RAY DIFFRACTION (1.348 Å)