PDBsum entry 6tyh

Hormone

PDB id: 6tyh

Contents

Protein chains

(+ 0 more) 22 a.a.

28 a.a.

29 a.a.

Ligands

IPH ×7

ACN ×2

GOL ×2

Metals

_CL ×2

_ZN ×2

Waters ×231

PDB id:

6tyh

Name:

Hormone

Title:

Four-disulfide insulin analog a22/b22

Structure:

Insulin a chain. Chain: a, c, e, g, i, k. Fragment: add engineered mutation instead of expression tag. Engineered: yes. Insulin b chain. Chain: b, d, f, h, j, l. Engineered: yes. Mutation: yes

Source:

Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Organism_taxid: 9606

Resolution:

1.60Å R-factor: 0.166 R-free: 0.196

Authors:

A.D.Blakely,X.Xiong

Key ref:

X.Xiong et al. (2020). Novel four-disulfide insulin analog with high aggregation stability and potency. Chem Sci, 11, 195-200. PubMed id: 32110371 DOI: 10.1039/c9sc04555d

Date:

08-Aug-19 Release date: 13-Nov-19

Protein chains

P01308  (INS_HUMAN) -  Insulin from Homo sapiens

Seq: 110 a.a.

Struc: 22 a.a.

Protein chain

P01308  (INS_HUMAN) -  Insulin from Homo sapiens

Seq: 110 a.a.

Struc: 28 a.a.*

Protein chains

P01308  (INS_HUMAN) -  Insulin from Homo sapiens

Seq: 110 a.a.

Struc: 29 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1039/c9sc04555d

Chem Sci 11:195-200 (2020)

PubMed id: 32110371

Novel four-disulfide insulin analog with high aggregation stability and potency.

X.Xiong, A.Blakely, P.Karra, M.A.VandenBerg, G.Ghabash, F.Whitby, Y.W.Zhang, M.J.Webber, W.L.Holland, C.P.Hill, D.H.Chou.

ABSTRACT

Although insulin was first purified and used therapeutically almost a century ago, there is still a need to improve therapeutic efficacy and patient convenience. A key challenge is the requirement for refrigeration to avoid inactivation of insulin by aggregation/fibrillation. Here, in an effort to mitigate this problem, we introduced a 4^th disulfide bond between a C-terminal extended insulin A chain and residues near the C-terminus of the B chain. Insulin activity was retained by an analog with an additional disulfide bond between residues A22 and B22, while other linkages tested resulted in much reduced potency. Furthermore, the A22-B22 analog maintains the native insulin tertiary structure as demonstrated by X-ray crystal structure determination. We further demonstrate that this four-disulfide analog has similar in vivo potency in mice compared to native insulin and demonstrates higher aggregation stability. In conclusion, we have discovered a novel four-disulfide insulin analog with high aggregation stability and potency.