PDBsum entry 4r1e

Protein binding/inhibitor

PDB id: 4r1e

Contents

Protein chains

142 a.a.

15 a.a.

Ligands

3EC

Waters ×67

PDB id:

4r1e

Name:

Protein binding/inhibitor

Title:

Crystal structure of mtip from plasmodium falciparum in complex with a peptide-fragment chimera

Structure:

Myosin a tail domain interacting protein. Chain: a. Fragment: unp residues 61-204. Engineered: yes. Myosin-a. Chain: b. Fragment: unp residues 803-816. Synonym: pfm-a. Engineered: yes

Source:

Plasmodium falciparum. Organism_taxid: 36329. Strain: isolate 3d7. Gene: mtip, pfl2225w. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Plasmodium falciparum isolate 3d7. Organism_taxid: 36329

Resolution:

1.98Å R-factor: 0.199 R-free: 0.223

Authors:

C.H.Douse,N.Vrielink,E.Cota,E.W.Tate

Key ref:

C.H.Douse et al. (2015). Targeting a dynamic protein-protein interaction: fragment screening against the malaria myosin A motor complex. Chemmedchem, 10, 134-143. PubMed id: 25367834 DOI: 10.1002/cmdc.201402357

Date:

05-Aug-14 Release date: 12-Nov-14

Protein chain

Q8I4W8  (Q8I4W8_PLAF7) -  Calmodulin from Plasmodium falciparum (isolate 3D7)

Seq: 204 a.a.

Struc: 142 a.a.

Protein chain

Q8IDR3  (MYOA_PLAF7) -  Myosin-A from Plasmodium falciparum (isolate 3D7)

Seq: 818 a.a.

Struc: 15 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1002/cmdc.201402357

Chemmedchem 10:134-143 (2015)

PubMed id: 25367834

Targeting a dynamic protein-protein interaction: fragment screening against the malaria myosin A motor complex.

C.H.Douse, N.Vrielink, Z.Wenlin, E.Cota, E.W.Tate.

ABSTRACT

Motility is a vital feature of the complex life cycle of Plasmodium falciparum, the apicomplexan parasite that causes human malaria. Processes such as host cell invasion are thought to be powered by a conserved actomyosin motor (containing myosin A or myoA), correct localization of which is dependent on a tight interaction with myosin A tail domain interacting protein (MTIP) at the inner membrane of the parasite. Although disruption of this protein-protein interaction represents an attractive means to investigate the putative roles of myoA-based motility and to inhibit the parasitic life cycle, no small molecules have been identified that bind to MTIP. Furthermore, it has not been possible to obtain a crystal structure of the free protein, which is highly dynamic and unstable in the absence of its natural myoA tail partner. Herein we report the de novo identification of the first molecules that bind to and stabilize MTIP via a fragment-based, integrated biophysical approach and structural investigations to examine the binding modes of hit compounds. The challenges of targeting such a dynamic system with traditional fragment screening workflows are addressed throughout.