PDBsum entry 6u8h

Transcription/inhibitor

PDB id: 6u8h

Contents

Protein chains

128 a.a.

13 a.a.

Ligands

GOL ×2

NH2

PE3

Metals

IOD ×6

Waters ×129

PDB id:

6u8h

Name:

Transcription/inhibitor

Title:

Brd2-bd1 in complex with the cyclic peptide 3.2_2

Structure:

Bromodomain-containing protein 2. Chain: a. Engineered: yes. Cyclic peptide 3.2_2. Chain: c. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd2. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.07Å R-factor: 0.184 R-free: 0.223

Authors:

K.Patel,J.L.Walshe,L.J.Walport,J.P.Mackay

Key ref:

K.Patel et al. (2020). Cyclic peptides can engage a single binding pocket through highly divergent modes. Proc Natl Acad Sci U S A, 117, 26728-26738. PubMed id: 33046654 DOI: 10.1073/pnas.2003086117

Date:

05-Sep-19 Release date: 19-Aug-20

Protein chain

P25440  (BRD2_HUMAN) -  Bromodomain-containing protein 2 from Homo sapiens

Seq: 801 a.a.

Struc: 128 a.a.*

Protein chain

No UniProt id for this chain

Struc: 12 a.a.

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

DOI no: 10.1073/pnas.2003086117

Proc Natl Acad Sci U S A 117:26728-26738 (2020)

PubMed id: 33046654

Cyclic peptides can engage a single binding pocket through highly divergent modes.

K.Patel, L.J.Walport, J.L.Walshe, P.D.Solomon, J.K.K.Low, D.H.Tran, K.S.Mouradian, A.P.G.Silva, L.Wilkinson-White, A.Norman, C.Franck, J.M.Matthews, J.M.Guss, R.J.Payne, T.Passioura, H.Suga, J.P.Mackay.

ABSTRACT

Cyclic peptide library screening technologies show immense promise for identifying drug leads and chemical probes for challenging targets. However, the structural and functional diversity encoded within such libraries is largely undefined. We have systematically profiled the affinity, selectivity, and structural features of library-derived cyclic peptides selected to recognize three closely related targets: the acetyllysine-binding bromodomain proteins BRD2, -3, and -4. We report affinities as low as 100 pM and specificities of up to 10⁶-fold. Crystal structures of 13 peptide-bromodomain complexes reveal remarkable diversity in both structure and binding mode, including both α-helical and β-sheet structures as well as bivalent binding modes. The peptides can also exhibit a high degree of structural preorganization. Our data demonstrate the enormous potential within these libraries to provide diverse binding modes against a single target, which underpins their capacity to yield highly potent and selective ligands.