PDBsum entry 6t7h

Hydrolase

PDB id: 6t7h

Contents

Protein chains

30 a.a.

258 a.a.

34 a.a.

Ligands

NAG ×2

EDO ×3

MRQ ×2

Metals

_NA ×2

Waters ×153

PDB id:

6t7h

Name:

Hydrolase

Title:

Crystal structure of thrombin in complex with macrocycle n14-pr4-a

Structure:

Thrombin light chain. Chain: a, l. Other_details: missing density. Thrombin heavy chain. Chain: b, h. Other_details: missing density

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organism_taxid: 9606

Resolution:

2.32Å R-factor: 0.196 R-free: 0.239

Authors:

A.Angelini,M.G.Kumar,C.Heinis,L.Cendron

Key ref:

G.K.Mothukuri et al. (2020). Macrocycle synthesis strategy based on step-wise "adding and reacting" three components enables screening of large combinatorial libraries. Chem Sci, 11, 7858-7863. PubMed id: 34094158 DOI: 10.1039/d0sc01944e

Date:

22-Oct-19 Release date: 30-Sep-20

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 30 a.a.

Protein chains

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 258 a.a.

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 34 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, L, H: E.C.3.4.21.5 - thrombin.
• Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

DOI no: 10.1039/d0sc01944e

Chem Sci 11:7858-7863 (2020)

PubMed id: 34094158

Macrocycle synthesis strategy based on step-wise "adding and reacting" three components enables screening of large combinatorial libraries.

G.K.Mothukuri, S.S.Kale, C.L.Stenbratt, A.Zorzi, J.Vesin, J.Bortoli Chapalay, K.Deyle, G.Turcatti, L.Cendron, A.Angelini, C.Heinis.

ABSTRACT

Macrocycles provide an attractive modality for drug development, but generating ligands for new targets is hampered by the limited availability of large macrocycle libraries. We have established a solution-phase macrocycle synthesis strategy in which three building blocks are coupled sequentially in efficient alkylation reactions that eliminate the need for product purification. We demonstrate the power of the approach by combinatorially reacting 15 bromoacetamide-activated tripeptides, 42 amines, and 6 bis-electrophile cyclization linkers to generate a 3780-compound library with minimal effort. Screening against thrombin yielded a potent and selective inhibitor (K_i = 4.2 ± 0.8 nM) that efficiently blocked blood coagulation in human plasma. Structure-activity relationship and X-ray crystallography analysis revealed that two of the three building blocks acted synergistically and underscored the importance of combinatorial screening in macrocycle development. The three-component library synthesis approach is general and offers a promising avenue to generate macrocycle ligands to other targets.