HPQ(His-Pro-Gln) -streptavidin binding motif

Understanding the HPQ (His-Pro-Gln) – Streptavidin Binding Motif

Streptavidin is a biotin-binding protein that is widely used for various purposes, including protein purification, biotinylation detection, and molecular imaging. One of the key features of streptavidin is its exceptionally high binding affinity for biotin, which enables sensitive and specific detection or isolation of biotinylated molecules. To utilize the streptavidin-biotin system effectively, one needs to understand its binding mechanism and also how to engineer or exploit it for specific applications. In this post, we will focus on one of the common binding motifs for streptavidin: the HPQ (Histidine-Proline-Glutamine) motif.

What is HPQ?

HPQ is a short peptide sequence (three amino acids) that has been identified as a reoccurring motif in many streptavidin-binding proteins or peptides. The HPQ motif can bind tightly to streptavidin, although not as strongly as biotin does. The HPQ-streptavidin interaction occurs at a different site on streptavidin than where biotin binds, providing a useful alternative for biotin-free detection or isolation of target molecules.

How does HPQ bind to streptavidin?

The HPQ-streptavidin interaction is mediated mainly by hydrogen bonds and hydrophobic interactions. The histidine (H) residue in HPQ can form a hydrogen bond with a tyrosine residue in streptavidin, while the proline (P) residue can fit snugly into a pocket in streptavidin through hydrophobic interactions with aromatic residues. The glutamine (Q) residue in HPQ does not directly interact with streptavidin but can contribute to the stability of the peptide conformation and its solubility.

How to use HPQ-streptavidin binding?

The HPQ-streptavidin binding motif has been used for various applications, such as targeted drug delivery, cell imaging, and biosensing. For example, researchers have fused HPQ-containing peptides to drug carriers or nanoparticles to enhance their specific delivery to cancer cells expressing streptavidin receptors. They have also attached HPQ-containing peptides to fluorescent dyes or quantum dots for imaging or tracking of cells or molecules in vitro or in vivo. In addition, HPQ-containing peptides have been used in biosensors for detection of analytes such as proteins, nucleic acids, or small molecules, by conjugating them to reporter molecules such as enzymes or fluorophores.


The HPQ (His-Pro-Gln) motif is a useful alternative to biotin for specific binding to streptavidin. It offers a versatile tool for various applications in biotechnology, from drug delivery to sensing. However, the strength and specificity of HPQ-streptavidin binding may vary depending on the sequence and context of the peptide or protein of interest. Therefore, it is important to optimize and validate the binding conditions and to compare HPQ-based approaches with biotin-based ones for their respective advantages and limitations.