This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
Sandbox454
From Proteopedia
Pembrolizumab
|
This is a default text for your page Sandbox454. Click above on edit this page to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia [1] or to the article describing Jmol [2] to the rescue.
Structure and Function
Pembrolizumab, or Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The Fc domain is glycosylated at both CH2 domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible and facing the solvent. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but can be conquered by introducing a serine-to-proline mutation at amino acid 228, which prevents Fab-arm exchange and stabilizes the molecule [3].
Pembrolizumab/PD-1 Interaction
In order for pembrolizumab to block PD-1, pembrolizumab forms a large, flat paratope (antigen-binding site) that can sustain PD-1’s large epitope (where antibody attaches on antigen). The induced interaction between pembrolizumab and PD-1 gives rise to a surface conformational change on PD-1. The new structure of PD-1 becomes a very shallow, “crescent”-like shape, in contrast to it’s flat conformation when bound to PD-L1 [4]
