PDBsum entry 6dpy

Hydrolase/hydrolase inhibitor

PDB id: 6dpy

Contents

Protein chains

358 a.a.

Ligands

H7A ×2

Waters ×237

PDB id:

6dpy

Name:

Hydrolase/hydrolase inhibitor

Title:

X-ray crystal structure of ampc beta-lactamase with inhibitor

Structure:

Beta-lactamase. Chain: a, b. Synonym: cephalosporinase. Engineered: yes

Source:

Escherichia coli (strain k12). Organism_taxid: 83333. Strain: k12. Gene: ampc, ampa, b4150, jw4111. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.91Å R-factor: 0.196 R-free: 0.232

Authors:

I.Singh

Key ref:

J.Lyu et al. (2019). Ultra-large library docking for discovering new chemotypes. Nature, 566, 224-229. PubMed id: 30728502 DOI: 10.1038/s41586-019-0917-9

Date:

09-Jun-18 Release date: 04-Jul-18

Protein chains

P00811  (AMPC_ECOLI) -  Beta-lactamase from Escherichia coli (strain K12)

Seq: 377 a.a.

Struc: 358 a.a.

Enzyme reactions

• Enzyme class: E.C.3.5.2.6 - beta-lactamase.
• Pathway: Penicillin Biosynthesis and Metabolism
• Reaction: a beta-lactam + H2O = a substituted beta-amino acid
• Cofactor: Zn(2+)

DOI no: 10.1038/s41586-019-0917-9

Nature 566:224-229 (2019)

PubMed id: 30728502

Ultra-large library docking for discovering new chemotypes.

J.Lyu, S.Wang, T.E.Balius, I.Singh, A.Levit, Y.S.Moroz, M.J.O'Meara, T.Che, E.Algaa, K.Tolmachova, A.A.Tolmachev, B.K.Shoichet, B.L.Roth, J.J.Irwin.

ABSTRACT

Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC β-lactamase (AmpC) and the D₄ dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D₄ dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D₄ dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D₄ dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D₄ dopamine receptor.